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Identity-by-Descent Analysis Reveals Susceptibility Loci for Severe Acne in Chinese Han Cohort

  • Author Footnotes
    12 These authors contributed equally to this work.
    Xingyan Yang
    Footnotes
    12 These authors contributed equally to this work.
    Affiliations
    State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, China
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  • Author Footnotes
    12 These authors contributed equally to this work.
    Wenjuan Wu
    Footnotes
    12 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Institute of Dermatology and Venereology of Yunnan Province, Kunming, China
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  • Author Footnotes
    12 These authors contributed equally to this work.
    Minsheng Peng
    Footnotes
    12 These authors contributed equally to this work.
    Affiliations
    State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China

    Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China

    KIZ/CUHK Joint Laboratory of Bio-Resources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
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  • Quankuan Shen
    Affiliations
    State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China

    Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China
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  • Jiaqi Feng
    Affiliations
    Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Institute of Dermatology and Venereology of Yunnan Province, Kunming, China
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  • Wei Lai
    Affiliations
    Department of Dermatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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  • Huilan Zhu
    Affiliations
    Guangzhou Institute of Dermatology, Guangzhou, China
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  • Caixia Tu
    Affiliations
    Department of Dermatology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
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  • Xiaorong Quan
    Affiliations
    Guilin Skin Disease Prevention and Treatment Hospital, Guilin, China
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  • Yihong Chen
    Affiliations
    Department of Dermatology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China
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  • Lanying Qin
    Affiliations
    Department of Dermatology, Cangzhou People's Hospital, Cangzhou, China
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  • Donglin Li
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    Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Institute of Dermatology and Venereology of Yunnan Province, Kunming, China
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  • Li He
    Correspondence
    Corresponding author
    Affiliations
    Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Institute of Dermatology and Venereology of Yunnan Province, Kunming, China
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  • Yaping Zhang
    Correspondence
    Corresponding author
    Affiliations
    State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, China

    State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China

    Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, China

    KIZ/CUHK Joint Laboratory of Bio-Resources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
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  • Author Footnotes
    12 These authors contributed equally to this work.
Open ArchivePublished:March 25, 2019DOI:https://doi.org/10.1016/j.jid.2019.03.1132

      Abbreviations:

      GWAS (genome-wide association study), IBD (identity-by-descent), SNP (single nucleotide polymorphism)
      To the Editor
      Acne (OMIM#604324), a complex skin disorder, can cause low self-esteem, depression, and even generate social handicaps for patients (
      • Bataille V.
      • Snieder H.
      • MacGregor A.
      • Sasieni P.
      • Spector T.
      The influence of genetics and environmental factors in the pathogenesis of acne: a twin study of acne in women.
      ). According to the Pillsbury grading system, acne can be classified into four grades (
      • Witkowski J.A.
      • Parish L.C.
      The assessment of acne: an evaluation of grading and lesion counting in the measurement of acne.
      ). Grade IV, severe acne, is characterized by a wide range of inflammatory lesions, such as nodules, cysts, and scars, in most cases. The pathogenesis of severe acne is attributed to multiple genetic and environmental factors (
      • Zouboulis C.
      • Eady A.
      • Philpott M.
      • Goldsmith L.
      • Orfanos C.
      • Cunliffe W.
      • et al.
      What is the pathogenesis of acne?.
      ). Over the last 2 decades, massive efforts have been made to explore the genetic basis for acne. Using the genome-wide association study (GWAS) approach,
      • Zhang M.
      • Qureshi A.A.
      • Hunter D.J.
      • Han J.
      A genome-wide association study of severe teenage acne in European Americans.
      identified a susceptibility locus at 8q24 (MYC, rs4133274, P = 1.7 × 10−6) associated with severe acne in European Americans. A few years ago, our research group identified two susceptibility loci at 11p11.2 (DDB2, rs747650, P = 4.41 × 10-9 and rs1060573, P = 1.28 × 10−8) and 1q24.2 (SELL, rs7531806, P = 1.20 × 10−8) among a cohort of Chinese Han (
      • He L.
      • Wu W.-J.
      • Yang J.-K.
      • Cheng H.
      • Zuo X.-B.
      • Lai W.
      • et al.
      Two new susceptibility loci 1q24. 2 and 11p11. 2 confer risk to severe acne.
      ). Moreover, a study based on a cohort of participants from the United Kingdom identified three susceptibility loci at 11q13.1 (OVOL1, rs478304, P = 3.23 × 10−11), 5q11.2 (FST, rs38055, P = 4.58 × 10−9), and 1q41 (TGFB2, rs1159268, P = 4.08 × 10−8) (
      • Navarini A.A.
      • Simpson M.A.
      • Weale M.
      • Knight J.
      • Carlavan I.
      • Reiniche P.
      • et al.
      Genome-wide association study identifies three novel susceptibility loci for severe acne vulgaris.
      ). These results suggest that the susceptibility loci for severe acne vary with ethnicity. However, the majority of genetic variants discovered for severe acne represent only a part of the total heritability, suggesting that additional genetic variants are yet to be discovered.
      Identity-by-descent (IBD) analysis, in terms of identifying continuous genetic segments (i.e., IBD segments) inherited from a common ancestor with higher frequency among cases than among controls (
      • Browning S.R.
      • Browning B.L.
      Identity by descent between distant relatives: detection and applications.
      ), has a higher power than traditional GWAS in uncovering diseases’ susceptibility loci, especially when multiple rare variants within a region are implicated (
      • Browning S.R.
      • Thompson E.A.
      Detecting rare variant associations by identity-by-descent mapping in case-control studies.
      ). IBD strategy can delineate more precisely the target regions for subsequent sequencing and point out exactly which samples are potential carriers (
      • Browning S.R.
      • Browning B.L.
      Identity by descent between distant relatives: detection and applications.
      ). As a result, the IBD approaches have been applied to analyze GWAS data for fine mapping of casual variants in various diseases, including type 1 diabetes (
      • Browning S.R.
      • Thompson E.A.
      Detecting rare variant associations by identity-by-descent mapping in case-control studies.
      ), multiple sclerosis (
      • Lin R.
      • Charlesworth J.
      • Stankovich J.
      • Perreau V.M.
      • Brown M.A.
      • Taylor B.V.
      • et al.
      Identity-by-descent mapping to detect rare variants conferring susceptibility to multiple sclerosis.
      ,
      • Westerlind H.
      • Imrell K.
      • Ramanujam R.
      • Myhr K.-M.
      • Celius E.G.
      • Harbo H.F.
      • et al.
      Identity-by-descent mapping in a scandinavian multiple sclerosis cohort.
      ), and familial adult myoclonus epilepsy (
      • Henden L.
      • Freytag S.
      • Afawi Z.
      • Baldassari S.
      • Berkovic S.F.
      • Bisulli F.
      • et al.
      Identity by descent fine mapping of familial adult myoclonus epilepsy (FAME) to 2p11.2-2q11.2.
      ). Herein, we employ the refined IBD approach (
      • Browning B.L.
      • Browning S.R.
      Improving the accuracy and efficiency of identity-by-descent detection in population data..
      ) to re-map the potential susceptibility genes for severe acne in the Chinese Han cohort.
      We first performed IBD mapping with the GWAS data set retrieved from our previous study (
      • He L.
      • Wu W.-J.
      • Yang J.-K.
      • Cheng H.
      • Zuo X.-B.
      • Lai W.
      • et al.
      Two new susceptibility loci 1q24. 2 and 11p11. 2 confer risk to severe acne.
      ). After quality control (detailed in Supplementary Materials and Methods online), a total of 798,700 autosomal single nucleotide polymorphisms (SNPs) in 1,024 cases and 1,029 controls were retained for subsequent analyses. The principal component analysis (PCA) showed no substantial stratification between the cases and controls (Supplementary Figure S1a online). A total of 22,640,240 autosomal IBD segments were identified by the refined IBD. More than 99% of the segments (22,565,113 of 22,640,240) were <8 cm in length. The IBD segments approximated a Pareto distribution (Figure 1a). After filtering out regions with logarithm of odds score <3, we performed permutation analysis of SNPs from IBD mapping, which indicated a wide distribution of significant markers across the genomes (Figure 1b). The top 0.05% SNPs in permutation analysis, that is 187 SNPs in total, were identified as significant candidates (Supplementary Table S1 online). After genomic position mapping of the SNPs, we marked 133 genes in total, located within 500 kb upstream/downstream of those candidate SNPs (Supplementary Table S2 online). We then assessed IBD sharing, in which we considered IBD segments (>1 cm) with full coverage or partial overlap with each of the 133 genes. Of the 133 genes, 74 had more frequent IBD sharing in the case–case than in control–control comparisons. According to the references, we then identified the following six candidate genes: TP63, F13A1, DDB2, CACNA1H, CMIP, and CDH13 that related to severe acne or the metabolism of androgen or sebum (Supplementary Table S2). Because telomeric segments are likely to be false positives (
      • Browning S.R.
      • Thompson E.A.
      Detecting rare variant associations by identity-by-descent mapping in case-control studies.
      ), we evaluated the IBD segments linked with the six candidate genes, and confirmed that none of them were located in or near telomeres.
      Figure thumbnail gr1
      Figure 1Permutation analysis after filtering regions with low IBD sharing. (a) The distribution of detected lengths of IBD segments <8 cm. (b) Permutation analysis of the significant markers.
      To further validate the risk loci for severe acne, we selected 131 SNPs from the 187 top-most SNPs detected in permutation analysis from IBD mapping and 369 SNPs (Supplementary Table S3 online) covering the six candidate risk genes. A total of 475 SNPs among them were successfully customized (Infinium Exome-24 v1.0 BeadChip; Illumina, San Diego, CA) and genotyped in 1,150 severe acne cases and 802 matched controls of the Chinese Han cohort. Additionally, 4,405 matched controls typed on Human Exome Asian BeadChip (Illumina) were added. After merging the two data sets and quality control (Supplementary Material and Methods), 287 SNPs for the independent replication samples (i.e., 1,124 cases and 5,180 controls) were retained. No evidence of population stratification between cases and controls was observed (Supplementary Figure S1b). Twenty-three SNPs showed statistical significance (P < 0.05, χ2 test) between cases and controls (Table 1). When considering a more stringent threshold of P < 0.005 (
      • Benjamin D.J.
      • Berger J.O.
      • Johannesson M.
      • Nosek B.A.
      • Wagenmakers E.J.
      • Berk R.
      • et al.
      Redefine statistical significance.
      ), four loci harboring BAZ2B, DDB2, CDH13, and F13A1 remained statistically significant. Only 11p11.2 (DDB2, rs10838662, Preplication = 7.42 × 10–5) and 6p25 (F13A1, rs435048, Preplication = 1.54 × 10–4) were significant after Bonferroni correction (Pcorrection = 0.05 / [287 – 1] = 1.75 × 10–4). The false discovery rate for both loci was <0.05 (Supplementary Table S4 online). F13A1 encodes a subunit of plasma coagulation factor XIII, which is essential in the final stages of blood coagulation and regulation of fibrinolysis (
      • Schweighofer N.
      • Lerchbaum E.
      • Trummer O.
      • Schwetz V.
      • Pilz S.
      • Pieber T.
      • et al.
      Androgen levels and metabolic parameters are associated with a genetic variant of F13A1 in women with polycystic ovary syndrome.
      ). The Val34Leu polymorphism in F13A1 could upregulate plasma levels of IL-6 (
      • Marín F.
      • Corral J.
      • Roldán V.
      • González-Conejero R.
      • del Rey M.L.
      • Sogorb F.
      • et al.
      Factor XIII Val34Leu polymorphism modulates the prothrombotic and inflammatory state associated with atrial fibrillation.
      ), which plays important roles in cytokine-mediated immune responses during the pathogenesis of acne (
      • Zouboulis C.
      • Eady A.
      • Philpott M.
      • Goldsmith L.
      • Orfanos C.
      • Cunliffe W.
      • et al.
      What is the pathogenesis of acne?.
      ). We propose the F13A1 as a novel susceptibility gene for server acne in Chinese Han cohort.
      Table 1Significant association (P < 0.05) of 23 single nucleotide polymorphism with severe acne in the replication
      CHRSNPsPosition (GRCH37.p13)MAFP-ValueOR (95% CI)Gene
      2rs752020921603832930.0363.434 × 10–3
      Statistically significant at 0.005 level.
      1.387 (1.113–1.728)BAZ2B
      4rs76603451879214990.3113.68 × 10–21.107 (1.006–1.217)
      4rs21006951829321980.2824.39 × 10–20.900 (0.812–0.997)
      4rs11544691003561790.2394.85 × 10–21.111 (1.001–1.233)ADH7
      6rs43504861676210.0611.54 × 10–4
      Statistically significant at 0.005 level.
      ,
      Statistically significant after the Bonferroni correction (Pcorrection = 0.05 / [287 – 1] = 1.75 × 10–4).
      1.371 (1.164–1.616)F13A1
      7rs17405238367723920.0177.93 × 10–31.447 (1.10–1.903)
      10rs4749190271150390.1321.73 × 10–21.170 (1.028–1.331)ABI1
      11rs10838662471841170.47.42 × 10–5
      Statistically significant at 0.005 level.
      ,
      Statistically significant after the Bonferroni correction (Pcorrection = 0.05 / [287 – 1] = 1.75 × 10–4).
      1.205 (1.099–1.321)DDB2
      11rs10769226469848030.3943.31 × 10–4
      Statistically significant at 0.005 level.
      ,
      Statistically significant after false discovery rate estimation.
      1.184 (1.080–1.299)DDB2
      11rs4494268470382200.3964.86 × 10–4
      Statistically significant at 0.005 level.
      ,
      Statistically significant after false discovery rate estimation.
      1.178 (1.074–1.292)DDB2
      11rs747650471760050.351.41 × 10–3
      Statistically significant at 0.005 level.
      1.166 (1.061–1.282)DDB2
      11rs7103581470728050.3424.03 × 10–3
      Statistically significant at 0.005 level.
      1.151 (1.046–1.266)
      11rs2291120472376800.0431.31 × 10–21.323 (1.060–1.652)DDB2
      13rs9571771679331310.3582.18× 10–20.894 (0.812–0.984)
      13rs9578163309277690.3673.73 × 10–21.104 (1.006–1.211)
      16rs9319570815794330.0384.27 × 10–21.256 (1.007–1.566)CMIP
      16rs8056448832817070.0259.28 × 10–4
      Statistically significant at 0.005 level.
      ,
      Statistically significant after false discovery rate estimation.
      1.540 (1.190–1.992)CDH13
      16rs7198542832940530.4043.79 × 10–4
      Statistically significant at 0.005 level.
      ,
      Statistically significant after false discovery rate estimation.
      0.842 (0.766–0.925)CDH13
      16rs17674675829356710.052.95 × 10–21.236 (1.021–1.496)CDH13
      16rs17195894833198820.1215.64 × 10–31.200 (1.055–1.366)CDH13
      16rs1108698830057080.0351.11 × 10–3
      Statistically significant at 0.005 level.
      ,
      Statistically significant after false discovery rate estimation.
      1.405 (1.144–1.725)CDH13
      16rs4782814835697870.4023.58 × 10–21.103 (1.007–1.209)CDH13
      16rs8054845834873160.2152.75 × 10–20.878 (0.783–0.985)CDH13
      Abbreviations: CHR, chromosome; CI, confidence interval; MAF, minor allele frequency; OR, odds ratio.
      1 Statistically significant at 0.005 level.
      2 Statistically significant after the Bonferroni correction (Pcorrection = 0.05 / [287 – 1] = 1.75 × 10–4).
      3 Statistically significant after false discovery rate estimation.
      For SNPs with peak signals in permutation analysis, we further conducted a meta-analysis integrating results of permutation analysis from IBD mapping and independent genotyping to check for its heterogeneity (Supplementary Table S1). Five SNPs referring to DDB2, including rs747650 (Pmeta = 8.10 × 10–7) identified in GWAS before (
      • He L.
      • Wu W.-J.
      • Yang J.-K.
      • Cheng H.
      • Zuo X.-B.
      • Lai W.
      • et al.
      Two new susceptibility loci 1q24. 2 and 11p11. 2 confer risk to severe acne.
      ), were validated by the meta-analysis. The SNP rs1154469 of ADH7, identified in our IBD mapping (PIBD = 1.55 × 10–4) and subsequent genotyping (Preplication =4.85 × 10–2), was significant in the meta-analysis (Pmeta = 1.35 × 10–4), suggesting 4q23 (ADH7, rs1154469) as a novel susceptibility loci for severe acne. Nevertheless, the other loci were not statistically significant in the meta-analysis (Pmeta > 0.05). DDB2 reported in our previous GWAS (
      • He L.
      • Wu W.-J.
      • Yang J.-K.
      • Cheng H.
      • Zuo X.-B.
      • Lai W.
      • et al.
      Two new susceptibility loci 1q24. 2 and 11p11. 2 confer risk to severe acne.
      ) is validated by the IBD approach, another reported susceptibility gene SELL was detected in IBD mapping, but the SNPs ranked out of the top 0.05% in the permutation analysis. It suggests that the IBD mapping is practical and efficient in GWAS data analysis.
      In summary, in addition to validating DDB2 (rs10838662), we identified two susceptibility loci at 6p25 (F13A1, rs435048) and 4q23 (ADH7, rs1154469) for severe acne in the Chinese Han cohort. The results extend our previous GWAS work (
      • He L.
      • Wu W.-J.
      • Yang J.-K.
      • Cheng H.
      • Zuo X.-B.
      • Lai W.
      • et al.
      Two new susceptibility loci 1q24. 2 and 11p11. 2 confer risk to severe acne.
      ), and provide candidate targets for future research. To discern the roles of F13A1 and ADH7 in the pathogenesis of severe acne, integration of various genetic, genomic, and functional analyses is still required.

      Data Availability

      The two genotype data reported here have been deposited in the Genome Variation Map in Big Data Center (http://bigd.big.ac.cn/gvm/; accession numbers GVM000024).

      Conflict of Interest

      The authors state no conflict of interest

      Acknowledgments

      We are grateful for the collaboration and volunteers to participating in this research. We thank Newton O. Otecko for reviewing our manuscript. This study was supported by grants from the National Natural Science Foundation of China ( U1402223 , 81460469 , 81760559 , 81360234 ) and Bureau of Science and Technology of Yunnan Province ( 2017HA010 , 2017FB117 , D-201612 ). MP thanks the Youth Innovation Promotion Association, Chinese Academy of Sciences for support.

      Author Contribution

      Conceptualization: LH, WW, MP, YZ; Resources: LH, WL, HZ, CT, XQ, YC, LQ; Validation: WW, JF, DL; Methodology: XY; Formal Analysis: QS; Writing - Original Draft Preparation: XY; Writing - Review and Editing: XY, WW, MP, QS, JF, WL, HZ, CT, XQ, YC, LQ, DL, LH, YZ.

      Supplementary Materials and Methods

      Study subjects

      The study was approved by the institutional ethics committee of the First Affiliated Hospital of Kunming Medical University. All procedures performed in studies involving human participants were approved by the institutional ethics committee of each hospital and was conducted according to the principles of the Declaration of Helsinki. The GWAS data set was retrieved from our previous study (
      • He L.
      • Wu W.-J.
      • Yang J.-K.
      • Cheng H.
      • Zuo X.-B.
      • Lai W.
      • et al.
      Two new susceptibility loci 1q24. 2 and 11p11. 2 confer risk to severe acne.
      ). For independent genotyping validation, peripheral blood samples of 1,150 unrelated cases with severe acne and 5,207 unrelated controls were collected. All cases were diagnosed as grade IV, according to the Pillsbury grading system (
      • Witkowski J.A.
      • Parish L.C.
      The assessment of acne: an evaluation of grading and lesion counting in the measurement of acne.
      ). All controls were healthy individuals without acne, systemic disorders, autoimmune diseases, or family history of severe acne. All samples were of self-reported Chinese Han origin.

      GWAS data analysis and quality control

      The GWAS data include 900,015 markers for 2,062 individuals with genotyped by using HumanOmniZhongHua-8 BeadChip, version 1.0 (Illumina). We exported the chip data in accordance with the reference sequence GRCh37 into PLINK format via GenomeStudio (Illumina). The markers on mitochondrial DNA and sex chromosomes were disregarded. We performed systematic quality control analysis (
      • Anderson C.A.
      • Pettersson F.H.
      • Clarke G.M.
      • Cardon L.R.
      • Morris A.P.
      • Zondervan K.T.
      Data quality control in genetic case-control association studies.
      ) using PLINK 1.9 (
      • Chang C.C.
      • Chow C.C.
      • Tellier L.C.
      • Vattikuti S.
      • Purcell S.M.
      • Lee J.J.
      Second-generation PLINK: rising to the challenge of larger and richer datasets.
      ). Nine samples (i.e., seven cases and two controls) were removed due to call rate <98%. The rest samples were confirmed to be unrelated by checking the pairwise identity by state. We adopted principal component analysis to test the matching degree of cases and controls (
      • Purcell S.
      • Neale B.
      • Todd-Brown K.
      • Thomas L.
      • Ferreira M.A.
      • Bender D.
      • et al.
      PLINK: a tool set for whole-genome association and population-based linkage analyses.
      ). After quality control, 1,024 cases and 1,029 controls remained for further analysis (Supplementary Figure S1). We excluded SNPs with the call rate <98%, minor allele frequency <0.01, or significant departure from Hardy-Weinberg equilibrium in controls (P < 1 × 10–6).

      IBD segment identification and pairwise IBD statistics

      We used SHAPEIT (v2.r727 ) (
      • Delaneau O.
      • Marchini J.
      1000 Genomes Project Consortium. Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel.
      ) to phase and impute the genotype data referring to the HapMap genetic map (
      • International HapMap C.
      • Frazer K.A.
      • Ballinger D.G.
      • Cox D.R.
      • Hinds D.A.
      • Stuve L.L.
      • et al.
      A second generation human haplotype map of over 3.1 million SNPs.
      ) and The 1000 Genomes phase 3 reference panel (The 1000
      • 1000 Genomes Project Consortium
      A map of human genome variation from population-scale sequencing.
      ). We detected the IBD segments using the Refined IBD algorithm (
      • Browning B.L.
      • Browning S.R.
      Refined IBD: a new method for detecting identity by descent in population samples.
      ) implemented in BEAGLE 4.1 (
      • Browning B.L.
      • Browning S.R.
      Improving the accuracy and efficiency of identity-by-descent detection in population data.
      ). Before the permutation, the segments with the logarithm of odds score <3 and the length <1 cm were excluded (
      • Westerlind H.
      • Imrell K.
      • Ramanujam R.
      • Myhr K.-M.
      • Celius E.G.
      • Harbo H.F.
      • et al.
      Identity-by-descent mapping in a scandinavian multiple sclerosis cohort.
      ). The P-values for the threshold for genome-wide significance was set the 0.05% of the distribution of the permutation. For the pairwise IBD statistics, we detected the distribution of IBD segments in case–case and control–control.

      Validation

      We extracted genomic DNA from peripheral blood samples by using FLexiGene kit (Qiagen, Hilden, Germany). To further validate the risk SNPs for severe acne, we selected 500 SNPs as candidates in the replication stage, including 131 SNPs from top 0.05% significant signal of permutation analysis (Supplementary Table S1) and 369 SNPs from six candidate genes (Supplementary Table S3). Among them, 475 SNPs (availability of data and materials) were successfully customized into the Infinium Exome-24 v1.0 BeadChip (Illumina), excluding three repeat SNPs and 22 unsuccessful designed SNPs. A total of 1,150 severe acne patients and 802 matched controls were genotyped. Samples with call rate <90% were disregarded in subsequent analysis. SNPs with call rate <90%, minor allele frequency <0.01, or significant departure from Hardy-Weinberg equilibrium in controls (P < 0.0001) were excluded. Seven SNPs were filtered by quality control. Meanwhile, we obtained the data for 4,405 ethnically matched controls independently genotyped on Human Exome Asian BeadChip (Illumina). We merged the two data sets to get 287 SNPs, including 128 SNPs from top 0.05% SNPs (Supplementary Table S1) and 159 SNPs from candidate genes (Supplementary Table S4) for 1,124 cases and 5,180 controls. The outliers were identified through principal component analysis using EIGENSOFT, version 6.1.4 (
      • Patterson N.
      • Price A.L.
      • Reich D.
      Population structure and eigenanalysis.
      ). We calculated χ2-based Cochran’s Q statistic to creating statistical significance (P < 0.05).
      Figure thumbnail fx1
      Supplementary Figure S1Principal components analysis for the genome-wide association study data set. (a) Principal component analyses of genome-wide association study samples (1,024 cases and 1,029 controls). (b) Principal component analyses of independent replication samples (1,124 cases and 5,180 controls).
      Supplementary Table S1Summary of association results for 187 single-nucleotide polymorphisms in the 0.05 percentile peak signals in the severe acne risk analysis
      CHRSNPsPosition (GRCH37.p13)Minor/ Major AlleleIBD MappingReplicationMeta-AnalysisGene/Near Gene
      MAFP-valueOR95% CIMAFP-valueOR95% CIP-valueOR95% CIQ
      CasesControlsPIBDLowerUpperCasesControlsPreplicationLowerUpperPmetaLowerUpper
      1kgp497927943209975A/G0.1910.1482.49E-041.3581.1531.6010.1730.1707.08E-011.0230.9081.1541.41E-021.1291.0731.1850.0064–/LEPRE1
      1kgp11234372159374636A/G0.0240.0117.84E-042.3211.4003.846–/FCER1A
      1rs2494184210386892A/G0.2920.3471.27E-040.7730.6780.8820.3090.3193.77E-010.9570.8681.0552.80E-030.8870.8430.9320.0108–/SERTAD4
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      2rs75202092160383293A/G0.0240.0479.39E-050.5070.3580.7170.0480.0353.43E-031.3871.1131.7286.84E-011.0390.9871.0910BAZ2B/–
      2rs1550068221826031A/G0.5020.4421.42E-041.2691.1221.4350.4790.4725.30E-011.0300.9401.1285.49E-031.1091.0541.1650.0074–/EPHA4
      3rs170375183885609G/A0.2000.1537.47E-051.3851.1781.6280.1860.1793.79E-011.0540.9381.1842.47E-031.1571.0991.2150.0072LRRN1/–
      3rs25968903915789A/C0.1670.1224.10E-051.4431.2101.7210.1520.1507.53E-011.0200.9001.1588.52E-031.1481.0901.2050.0017LOC101927236/–
      3rs26338203915943A/G0.1670.1224.97E-051.4371.2051.7130.1540.1517.25E-011.0230.9021.1598.29E-031.1471.0901.2050.002LOC101929731/–
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      3rs92406763644694A/G0.0920.1317.37E-050.6720.5520.8190.1100.1136.74E-010.9700.8391.1207.65E-030.8530.8110.8960.0033–/TRNAE27P
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      3rs6790258189344149A/G0.3490.4032.99E-040.7920.6980.8990.3740.3749.89E-011.0010.9111.0993.31E-020.9220.8750.9680.0035–/TP63
      3rs7631358189348411A/G0.3840.4484.13E-050.7710.6810.8730.4160.4158.95E-011.0060.9181.1032.00E-020.9160.8700.9620.0007TP63/–
      3rs7636839189356941A/G0.4470.5123.15E-050.7710.6820.8710.4740.4843.81E-010.9600.8771.0511.50E-030.8890.8440.9330.0047TP63/–
      3rs4600802189383430G/A0.3730.4292.41E-040.7910.6980.8970.3960.4007.12E-010.9830.8961.0781.30E-020.9100.8640.9550.0064TP63/–
      4rs7436952307574C/A0.3730.3146.67E-051.3021.1431.4820.3470.3405.46E-011.0300.9361.1324.37E-031.1181.0621.1740.0043ZFYVE28 /–
      4rs45743454748816G/A0.4050.3456.27E-051.2951.1411.4710.3830.3775.82E-011.0260.9351.1275.12E-031.1131.0571.1690.0037–/STX18-AS1
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      4kgp664415014217660A/G0.2390.1891.17E-041.3421.1551.5600.2130.2204.84E-010.9610.8611.0738.75E-021.0811.0261.1350.0004–/BOD1L1
      4rs1093953714234630A/G0.2180.1743.45E-041.3271.1361.5490.1900.1947.13E-010.9790.8721.0986.58E-021.0911.0361.1450.002–/–
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      4kgp330619125570751A/C0.3650.4193.28E-040.7940.7010.9010.3860.3935.65E-010.9730.8871.0689.41E-030.9060.8610.9510.0109–/SLC34A2
      4rs469211831678181A/G0.5090.4544.26E-041.2461.1031.4090.4670.4773.94E-010.9610.8781.0521.61E-011.0541.0011.1060.0009–/PCDH7
      4kgp1045748341022652G/A0.1500.1967.85E-050.7200.6120.8480.1890.1781.92E-011.0800.9621.2132.22E-010.9430.8960.9900.0001APBB2/–
      4rs1003324841030604C/A0.1490.1967.87E-050.7210.6120.8480.1890.1781.93E-011.0800.9621.2132.23E-010.9430.8960.9900.0001APBB2/–
      4rs1154469100356179A/G0.2640.2141.55E-041.3201.1431.5250.2540.2354.85E-021.1111.0011.2331.35E-04
      Statistically significant at 0.05 level in the discovery replication and combined studies, the lines have been marked in bold type.
      1.1791.1201.2380.0574ADH7/–
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      Statistically significant at 0.05 level in the discovery replication and combined studies, the lines have been marked in bold type.
      1.1641.1061.2230.0741–/–
      5kgp1728845128089238A/G0.0300.0123.19E-052.6431.6434.2510.0200.0207.88E-011.0450.7591.4401.38E-021.3971.3271.4660.0015–/FBN2
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      7rs1740523836772392A/G0.0240.0103.92E-042.5001.4814.2210.0300.0217.93E-031.4471.1001.9038.48E-05
      Statistically significant at 0.05 level in the discovery replication and combined studies, the lines have been marked in bold type.
      1.6281.5461.7090.0698–/–
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      10rs12573222133060988G/A0.0280.0511.95E-040.5420.3910.7520.0400.0417.85E-010.9680.7691.2201.91E-020.7980.7580.8380.0045TCERG1L/–
      10rs2918117133084992A/G0.1170.1607.57E-050.6980.5830.8340.1340.1433.10E-010.9340.8191.0661.60E-030.8430.8010.8850.0101TCERG1L /–
      11rs110284623629578C/A0.0720.1093.15E-050.6320.5080.7850.0940.0939.53E-011.0050.8601.1741.87E-020.8590.8160.9020.0007–/OR7E117P
      11rs107673173631058G/A0.0730.1094.65E-050.6390.5150.7940.0960.0947.14E-011.0290.8831.2004.13E-020.8780.8340.9220.0004–/–
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      11rs153572134500079G/A0.4910.4342.57E-041.2581.1121.4220.4670.4605.70E-011.0270.9381.1248.45E-031.1031.0481.1580.0092–/–
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      11rs1076922646984803G/A0.4220.3673.43E-041.2591.1101.4280.4090.3693.31E-041.1841.0801.2995.58E-07
      Statistically significant at 0.05 level in the discovery replication and combined studies, the lines have been marked in bold type.
      1.2101.1491.2700.4413–/DDB2
      11rs449426847038220G/A0.4240.3682.89E-041.2611.1121.4290.4110.3724.86E-041.1781.0741.2927.18E-07
      Statistically significant at 0.05 level in the discovery replication and combined studies, the lines have been marked in bold type.
      1.2061.1461.2670.391–/ DDB2
      11rs710358147072805A/C0.3710.3138.06E-051.2971.1401.4760.3500.3184.03E-031.1511.0461.2663.16E-06
      Statistically significant at 0.05 level in the discovery replication and combined studies, the lines have been marked in bold type.
      1.2011.1411.2610.1457- /–
      11rs74765047176005G/A0.3800.3216.38E-051.3001.1431.4780.3600.3251.41E-031.1661.0611.2828.10E-07
      Statistically significant at 0.05 level in the discovery replication and combined studies, the lines have been marked in bold type.
      1.2111.1511.2720.1817–/DDB2
      11rs1083866247184117A/C0.4290.3711.85E-041.2711.1211.4420.4180.3747.42E-051.2051.0991.3216.46E-08
      Statistically significant at 0.05 level in the discovery replication and combined studies, the lines have been marked in bold type.
      1.2281.1661.2890.503- /DDB2
      11kgp595131264597201A/G0.1680.1283.91E-041.3701.1511.631CDC42BPG/–
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      12kgp6686686801414A/G0.2060.2552.20E-040.7600.6570.879–/WNK1
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      12rs206061439508651A/G0.2460.2953.72E-040.7780.6780.894–/KIF21A
      12kgp558707463196752G/A0.0860.0562.20E-041.5791.2372.0150.0670.0668.43E-011.0180.8501.2201.94E-021.1891.1301.2480.0046PPM1H/–
      12kgp275847468658918A/C0.5150.4582.58E-041.2571.1121.4210.5000.4862.21E-011.0580.9671.1591.63E-031.1241.0681.1810.0268–/IL26
      12rs735870691391478G/A0.2450.1982.92E-041.3141.1331.5240.2220.2219.28E-011.0050.9011.1212.68E-021.1041.0491.1590.0042EPYC/–
      12rs240842291428098G/A0.2480.2002.18E-041.3201.1391.5300.2250.2259.79E-010.9990.8961.1133.08E-021.1011.0461.1560.0028–/–
      12rs1077728491432518G/A0.2550.2061.47E-041.3261.1461.5350.2300.2319.74E-010.9980.8971.1112.67E-021.1031.0471.1580.0021–/KERA
      12rs1074554991441121A/G0.2480.2002.34E-041.3181.1381.528–/–
      13rs207701130884562A/G0.2300.2901.14E-050.7310.6350.8410.2730.2571.16E-011.0850.9801.2021.90E-010.9460.8990.9940–/KATNAL1
      13rs957816330927769A/G0.3370.3968.82E-050.7750.6830.8810.3880.3653.73E-021.1041.0061.2115.32E-010.9760.9271.0250LINC00426/–
      13rs1243007931554847G/A0.2390.2884.02E-040.7780.6770.8940.2540.2596.16E-010.9740.8781.0801.20E-020.8990.8540.9440.0112–/MEDAG
      13kgp490826546057719A/G0.2190.1711.24E-041.3551.1601.5830.2020.1922.79E-011.0640.9511.1921.79E-031.1571.0991.2150.0137COG3/–
      13rs799760261723115A/G0.0730.1061.60E-040.6590.5300.8190.0820.0911.85E-010.8960.7611.0549.24E-040.8020.7620.8420.0271–/PCDH20
      13rs953905761769280A/G0.0690.1081.01E-050.6110.4900.7620.0810.0892.18E-010.9020.7651.0633.14E-040.7850.7450.8240.0055–/MIR3169
      13rs959209661807409A/G0.0790.1151.22E-040.6640.5380.819MIR3169/–
      13rs957177167933131G/A0.3320.3844.17E-040.7940.6990.9030.3280.3542.18E-020.8940.8120.9847.71E-05
      Statistically significant at 0.05 level in the discovery replication and combined studies, the lines have been marked in bold type.
      0.8560.8140.8990.1494–/–
      13rs732057271204021A/C0.0310.0131.18E-042.3831.5123.7560.0140.0195.93E-020.6950.4751.0163.36E-011.1541.0961.2120–/SOGA2P1
      13rs232907678981531A/G0.2940.2454.26E-041.2821.1161.472RNF219-AS1/–
      13rs9517971100728201C/A0.1850.2303.01E-040.7560.6500.880–/–
      14kgp1073227326690430A/G0.1930.1524.87E-041.3351.1351.572–/CYB5AP5
      14kgp1186978234233909A/G0.0420.0673.12E-040.6030.4570.7960.0440.0521.42E-010.8500.6851.0567.94E-040.7470.7090.7840.0559NPAS3/–
      14kgp856011134237791G/A0.0500.0773.88E-040.6300.4880.815–/–
      14kgp185395478550328A/G0.1960.2432.62E-040.7590.6540.8800.2030.2161.71E-010.9250.8271.0341.02E-030.8610.8180.9040.0368–/–
      14rs1710683378556038G/A0.2010.2501.79E-040.7550.6520.8750.2100.2212.52E-010.9380.8391.0471.57E-030.8670.8240.9110.0212–/FRDAP
      15kgp1996231727532281G/A0.0960.0614.24E-051.6211.2842.0460.0770.0824.40E-010.9360.7911.1087.91E-021.1301.0741.1870.0002GABRG3/–
      15kgp201157180443757G/A0.0490.0271.53E-041.8891.3522.6390.0330.0356.51E-010.9440.7341.2136.04E-021.2121.1521.2730.0011–/FAH
      15kgp2004174797880882A/G0.0150.0331.55E-040.4410.2860.6820.0220.0245.57E-010.9120.6711.2409.13E-030.7160.6800.7520.0075–/LOC101927286
      16kgp111244951268542A/G0.0650.1049.91E-060.6030.4810.7560.0790.0809.37E-010.9930.8401.1747.58E-030.8330.7910.8740.0005CACNA1H/–
      16kgp80696001269003G/A0.0650.1031.40E-050.6070.4840.7620.0800.0809.99E-011.0000.8461.1821.05E-020.8390.7970.8810.0005CACNA1H/–
      16rs27388931269029A/G0.0990.1481.98E-060.6330.5230.7650.1080.1125.71E-010.9590.8301.1099.04E-040.8230.7820.8640.0006CACNA1H/–
      16rs9099211273803G/A0.1140.1629.17E-060.6660.5560.7980.1240.1304.33E-010.9470.8261.0859.85E-040.8330.7910.8740.0023TPSG1/–
      16kgp987771013158214A/C0.0560.0332.40E-041.7681.3002.405SHISA9/–
      16rs1697223619617573A/G0.1380.1802.49E-040.7300.6170.8640.1670.1698.33E-010.9870.8751.1142.14E-020.8910.8460.9360.0044C16orf62/–
      16rs1164753824929475G/A0.1820.1402.35E-041.3691.1571.6180.1530.1585.19E-010.9600.8471.0889.25E-021.0901.0351.1440.0009–/–
      16rs211083554507844A/G0.0720.1043.95E-040.6740.5410.839–/FTO
      16rs1244477881773227A/G0.0500.0278.90E-051.9381.3842.7130.0410.0396.47E-011.0550.8401.3251.10E-021.2781.2141.3410.0034–/CMIP
      16rs478300684572358C/A0.0960.1314.01E-040.7040.5790.856–/CDH13
      17kgp56005485844561G/A0.3980.3432.70E-041.2661.1151.437–/LOC339166
      17rs721346032522613A/G0.2260.1803.06E-041.3251.1371.5430.1990.2083.39E-010.9470.8461.0591.71E-011.0661.0121.1190.0005–/–
      17kgp469760332533423T/A0.3070.2531.17E-041.3081.1411.5000.2770.2826.30E-010.9760.8821.0795.79E-021.0821.0281.1360.0007–/CCL11
      17kgp446081232533694A/G0.3070.2531.17E-041.3081.1411.5000.2780.2826.89E-010.9800.8861.0835.00E-021.0851.0301.1390.0009–/–
      17rs75741238784927A/G0.4050.3461.27E-041.2821.1291.4560.3670.3679.88E-011.0010.9111.0992.23E-021.0921.0371.1470.0022SMARCE1/–
      17rs807359965367094G/A0.4090.4652.75E-040.7950.7030.9000.4150.4331.11E-010.9280.8471.0175.68E-040.8790.8350.9230.0487–/PSMD12
      17rs1165145670605514A/G0.0710.1024.47E-040.6740.5400.841–/–
      17kgp261043970613489A/G0.1640.2092.32E-040.7430.6350.871LINC00511/–
      18kgp124196499782671G/A0.1180.1573.64E-040.7220.6040.864RAB31/–
      18rs22675659804312A/C0.0820.1144.33E-040.6890.5590.848–/–
      18rs1260843229554990G/A0.2590.3131.58E-040.7690.6710.8820.3070.2876.11E-021.0990.9961.2124.92E-010.9720.9241.0210–/TRAPPC8
      18rs1260608429558592A/G0.2400.2931.49E-040.7640.6650.878–/–
      18rs722860361680926G/A0.2630.3205.83E-050.7580.6630.8680.2850.2806.69E-011.0220.9251.1304.05E-020.9190.8730.9650.0005–/–
      18rs185039261681644A/G0.2630.3206.14E-050.7590.6630.8690.2840.2806.69E-011.0220.9251.1304.11E-020.9200.8740.9650.0005–/–
      18rs140057661685918A/G0.2630.3205.16E-050.7560.6600.8660.2840.2796.64E-011.0220.9251.1303.91E-020.9190.8730.9650.0005–/HMSD
      20rs60456771941488G/A0.0090.0242.77E-040.3850.2260.6560.0170.0179.36E-011.0140.7181.4336.53E-020.7610.7230.7990.0028LOC727993/–
      20kgp193349285282850A/G0.0250.0511.64E-050.4800.3410.675PROKR2/–
      20rs481460417322385G/A0.4320.4874.15E-040.8010.7080.9060.4850.4691.78E-011.0640.9721.1653.14E-010.9630.9151.0110.0003PCSK2/–
      20rs202193517337814A/G0.4740.4183.68E-041.2511.1061.415–/–
      20rs608066117346807A/G0.4410.4963.90E-040.8010.7080.906–/–
      20rs101029117426687G/A0.2890.3395.17E-040.7910.6930.9030.3160.3273.22E-010.9520.8641.0494.36E-030.8920.8480.9370.027–/–
      21rs191062225561631G/A0.3020.3562.45E-040.7830.6870.893–/–
      21rs191062425566307A/G0.3000.3561.69E-040.7780.6830.8870.3270.3344.74E-010.9660.8771.0635.07E-030.8950.8500.9400.0093–/VN2R20P
      21kgp76977347557765A/G0.2290.1801.28E-041.3471.1561.5700.2200.2051.16E-011.0920.9781.2184.58E-041.1731.1141.2310.0288FTCD/–
      22kgp1057117824270129A/C0.1010.0692.90E-041.5061.2051.8810.0880.0834.17E-011.0680.9111.2545.77E-031.2011.1411.2610.014–/LOC100652871
      22rs73928126277148G/A0.4370.4951.68E-040.7900.6990.8930.4610.4629.56E-010.9980.9111.0922.29E-020.9190.8730.9650.0027MYO18B/–
      22kgp1247889827281209C/A0.2130.1573.24E-061.4571.2431.7080.1800.1787.87E-011.0170.9021.1452.66E-031.1571.1001.2150.0004–/RPL15P22
      22rs424227284022A/G0.1760.1341.59E-041.3881.1701.6450.1510.1476.18E-011.0330.9101.1728.06E-031.1471.0901.2040.0063–/RPL15P22
      22kgp1222078127287946G/A0.1750.1342.59E-041.3731.1581.6290.1530.1474.26E-011.0520.9281.1945.18E-031.1551.0981.2130.0138–/–
      Abbreviations: CHR, chromosome; CI, confidence interval; IBD, identity-by-descent; MAF, minor allele frequency; OR, odds ratio; Q, p-value for Cochrane's Q statistic; SNP, single nucleotide polymorphism.
      1 Statistically significant at 0.05 level in the discovery replication and combined studies, the lines have been marked in bold type.
      Supplementary Table S2The frequency of identity-by-descent segments shared in case–case and control–control assessments
      CHRSNPsPosition (GRCH37.p13)Gene/Near GeneLociCase–CaseControl–ControlReference
      8rs29249072731382–/CSMD18p23.34983948387NA
      16rs478300684572358–/CDH1316q241773317108
      • Wang H.
      • Guo M.
      • Shen S.
      • He L.
      • Zhang X.
      • Zuo X.
      • et al.
      Variants in SELL, MRPS36P2, TP63, DDB2, CACNA1H, ADAM19, GNAI1, CDH13 and GABRG2 interact to confer risk of acne in Chinese population.
      3kgp8576537159653993LOC101928376/–3q25.327832335NA
      7rs1740523836772392–/AOAH7p1432852863NA
      10rs1082329770845091–/SRGN10q22.120471661NA
      16rs1244477881773227–/CMIP16q2329242538
      • Grimbert P.
      • Valanciute A.
      • Audard V.
      • Lang P.
      • Guellaën G.
      • Sahali D.
      The Filamin-A is a partner of Tc-mip, a new adapter protein involved in c-maf-dependent Th2 signaling pathway.
      13rs953905761769280–/MIR316913q21.222461981NA
      13rs959209661807409MIR3169/–13q21.222461981NA
      12kgp558707463196752PPM1H/–12q1446344391NA
      10rs4919416101790389–/CPN110q24.1-24.321391907NA
      4rs13118519141851355RNF150/–4q31.1-31.220811857NA
      6rs17817856229348F13A1/–6p2520301812
      • Schweighofer N.
      • Lerchbaum E.
      • Trummer O.
      • Schwetz V.
      • Pilz S.
      • Pieber T.
      • et al.
      Androgen levels and metabolic parameters are associated with a genetic variant of F13A1 in women with polycystic ovary syndrome.
      6kgp61782546240689F13A1/–6p2520301812
      • Wang H.
      • Guo M.
      • Shen S.
      • He L.
      • Zhang X.
      • Zuo X.
      • et al.
      Variants in SELL, MRPS36P2, TP63, DDB2, CACNA1H, ADAM19, GNAI1, CDH13 and GABRG2 interact to confer risk of acne in Chinese population.
      2kgp16937219280826–/OSR12q2418951701NA
      1rs7543259239979186CHRM3/–1q4318521698NA
      10rs1222051616458636–/PTER10p13970818NA
      10rs1226619786721948–/RGR10q23.134383288NA
      10rs2944507133056853TCERG1L/–10q26.326362500NA
      10rs12573222133060988TCERG1L/–10q26.326362500NA
      10rs2918117133084992TCERG1L /–10q26.326362500NA
      8rs194790513527276–/DLC18p2225682435NA
      13rs232907678981531RNF219-AS1/–13q22-3132103092NA
      3rs9882796189330551–/TP633q2825772488
      • Wang H.
      • Guo M.
      • Shen S.
      • He L.
      • Zhang X.
      • Zuo X.
      • et al.
      Variants in SELL, MRPS36P2, TP63, DDB2, CACNA1H, ADAM19, GNAI1, CDH13 and GABRG2 interact to confer risk of acne in Chinese population.
      3rs6790258189344149–/TP633q2825772488
      • Wang H.
      • Guo M.
      • Shen S.
      • He L.
      • Zhang X.
      • Zuo X.
      • et al.
      Variants in SELL, MRPS36P2, TP63, DDB2, CACNA1H, ADAM19, GNAI1, CDH13 and GABRG2 interact to confer risk of acne in Chinese population.
      3rs7631358189348411TP63/–3q2825772488
      • Wang H.
      • Guo M.
      • Shen S.
      • He L.
      • Zhang X.
      • Zuo X.
      • et al.
      Variants in SELL, MRPS36P2, TP63, DDB2, CACNA1H, ADAM19, GNAI1, CDH13 and GABRG2 interact to confer risk of acne in Chinese population.
      3rs7636839189356941TP63/–3q2825772488
      • Wang H.
      • Guo M.
      • Shen S.
      • He L.
      • Zhang X.
      • Zuo X.
      • et al.
      Variants in SELL, MRPS36P2, TP63, DDB2, CACNA1H, ADAM19, GNAI1, CDH13 and GABRG2 interact to confer risk of acne in Chinese population.
      3rs4600802189383430TP63/–3q2825772488
      • Wang H.
      • Guo M.
      • Shen S.
      • He L.
      • Zhang X.
      • Zuo X.
      • et al.
      Variants in SELL, MRPS36P2, TP63, DDB2, CACNA1H, ADAM19, GNAI1, CDH13 and GABRG2 interact to confer risk of acne in Chinese population.
      16rs1697223619617573C16orf62/–16p12532447NA
      3rs170375183885609LRRN1/–3q26474393NA
      2rs466646019295604LOC105373457/–2q24338259NA
      21rs191062425566307–/VN2R20P21q21818NA
      4rs767257316481679–/LDB24p15.333233251NA
      11kgp595131264597201CDC42BPG/–11q13.1281210NA
      13kgp490826546057719COG3/–13q14.116091NA
      20rs481460417322385PCSK2/–20p1213541292NA
      4rs1154469100356179ADH7/–4q23441386NA
      6rs6930395139593772TXLNB /–6q24574519NA
      7kgp13809561156761145–/RNF327q36191142NA
      22kgp1057117824270129–/LOC10065287122q11.2989943NA
      15kgp1996231727532281GABRG3/–15q1218971853NA
      4rs469211831678181–/PCDH74p15.113241288NA
      12kgp275847468658918–/IL2612q15280245NA
      22kgp1247889827281209–/RPL15P2222q12.1264231NA
      22rs424227284022–/RPL15P2222q12.1264231NA
      18kgp124196499782671RAB31/–18p11.212521220NA
      2kgp613708810200316CYS1/GRHL12p2412292NA
      4kgp330619125570751–/SLC34A24p15.2153124NA
      11rs1076922646984803–/DDB211p11.2237211
      • He L.
      • Wu W.-J.
      • Yang J.-K.
      • Cheng H.
      • Zuo X.-B.
      • Lai W.
      • et al.
      Two new susceptibility loci 1q24. 2 and 11p11. 2 confer risk to severe acne.
      11rs449426847038220–/ DDB211p11.2237211
      • He L.
      • Wu W.-J.
      • Yang J.-K.
      • Cheng H.
      • Zuo X.-B.
      • Lai W.
      • et al.
      Two new susceptibility loci 1q24. 2 and 11p11. 2 confer risk to severe acne.
      11rs710358147072805–/ DDB211p11.2237211
      • He L.
      • Wu W.-J.
      • Yang J.-K.
      • Cheng H.
      • Zuo X.-B.
      • Lai W.
      • et al.
      Two new susceptibility loci 1q24. 2 and 11p11. 2 confer risk to severe acne.
      11rs74765047176005–/DDB211p11.2237211
      • He L.
      • Wu W.-J.
      • Yang J.-K.
      • Cheng H.
      • Zuo X.-B.
      • Lai W.
      • et al.
      Two new susceptibility loci 1q24. 2 and 11p11. 2 confer risk to severe acne.
      11rs1083866247184117- /DDB211p11.2237211
      • He L.
      • Wu W.-J.
      • Yang J.-K.
      • Cheng H.
      • Zuo X.-B.
      • Lai W.
      • et al.
      Two new susceptibility loci 1q24. 2 and 11p11. 2 confer risk to severe acne.
      3rs26338203915943LOC101929731/–3p268664NA
      18rs1260843229554990–/TRAPPC818q12.16548NA
      4rs45743454748816–/STX18-AS14p1618121796NA
      7kgp4743722139694149HUS1/–7p125947NA
      13rs1243007931554847–/MEDAG13q12.34836NA
      16rs211083554507844–/FTO16q12.223042293NA
      1kgp11234372159374636–/FCER1A1q232818NA
      12rs380914026278444–/BHLHE4112p12.1-11.27161NA
      16kgp111244951268542CACNA1H/–16p13.3359349
      • Wang H.
      • Guo M.
      • Shen S.
      • He L.
      • Zhang X.
      • Zuo X.
      • et al.
      Variants in SELL, MRPS36P2, TP63, DDB2, CACNA1H, ADAM19, GNAI1, CDH13 and GABRG2 interact to confer risk of acne in Chinese population.
      16kgp80696001269003CACNA1H/–16p13.3359349
      • Wang H.
      • Guo M.
      • Shen S.
      • He L.
      • Zhang X.
      • Zuo X.
      • et al.
      Variants in SELL, MRPS36P2, TP63, DDB2, CACNA1H, ADAM19, GNAI1, CDH13 and GABRG2 interact to confer risk of acne in Chinese population.
      16rs27388931269029CACNA1H/–16p13.3359349
      • Wang H.
      • Guo M.
      • Shen S.
      • He L.
      • Zhang X.
      • Zuo X.
      • et al.
      Variants in SELL, MRPS36P2, TP63, DDB2, CACNA1H, ADAM19, GNAI1, CDH13 and GABRG2 interact to confer risk of acne in Chinese population.
      3rs181135153098775SNTN/–3p21.2102NA
      17kgp56005485844561–/LOC33916617p1314311423NA
      17rs75741238784927SMARCE1/–17q21.1-21.22215NA
      17rs807359965367094–/PSMD1217q241913NA
      2rs75202092160383293BAZ2B/–2q24.120692064NA
      20kgp193349285282850PROKR2/–20p1272NA
      4kgp9291167165713760LOC100505989/–4q322117NA
      17kgp469760332533423–/CCL1117q1295NA
      11kgp742677920690111–/PRMT311p15.1118116NA
      4kgp30323126742329–/WFS14p1687NA
      18rs140057661685918–/HMSD18q222120NA
      17kgp261043970613489LINC00511/–17q24313313NA
      5kgp1728845128089238–/FBN25q23.3582583NA
      13rs732057271204021–/SOGA2P113q21.35051NA
      2rs234254717261089–/ZFYVE9P22p2402NA
      21kgp76977347557765FTCD/–21q22.325NA
      2kgp8990602114826920–/SEPHS1P72q133438NA
      1rs2494184210386892–/SERTAD41q32.21621NA
      12rs1077728491432518–/KERA12q21.31117NA
      4kgp664415014217660–/BOD1L14p15.38593NA
      12rs735870691391478EPYC/–12q21.32129NA
      12rs206061439508651–/KIF21A12q12120132NA
      1kgp497927943209975–/LEPRE11p34.3-34.11326NA
      15kgp201157180443757–/FAH15q25165178NA
      13rs957816330927769LINC00426/–13q12.3106120NA
      4rs977361182933601LOC101928703/–4q34-356986NA
      10kgp45677833327273–/CCSER210p15221238NA
      14kgp1073227326690430–/CYB5AP514q12705722NA
      16rs9099211273803TPSG1/–16p13.3582602NA
      20rs60456771941488LOC727993/–20p13153175NA
      7kgp13450646105838161–/SYPL17q226892NA
      10rs2149739110140197–/SORCS310q25.113471371NA
      2rs73588847200025TTC7A/–2p2111191144NA
      9rs47408235632721–/PDCD1LG29p2411421167NA
      13rs799760261723115–/PCDH2013q21.24975NA
      12kgp6686686801414–/WNK112p13.371106NA
      10rs12249758120032904–/CASC210q26.120722108NA
      11rs132369034500687ELF5/–11p13112150
      • Koyama K.
      • Takahara K.
      • Inamoto T.
      • Ibuki N.
      • Minami K.
      • Uehara H.
      • et al.
      E74-like factor inhibition induces reacquisition of hormone sensitiveness decreasing period circadian protein homolog 1 expression in prostate cancer cells.
      11rs794997234502042ELF5/–11p13112150
      • Koyama K.
      • Takahara K.
      • Inamoto T.
      • Ibuki N.
      • Minami K.
      • Uehara H.
      • et al.
      E74-like factor inhibition induces reacquisition of hormone sensitiveness decreasing period circadian protein homolog 1 expression in prostate cancer cells.
      5rs6896064156975016ADAM19/–5q33.3280322Wang et al. (2014)
      8kgp457039882443781FABP12/–8q21.14085NA
      10rs317489110022170LOC105378476/–10q25.112561301NA
      2kgp748426264355962PELI1/–2p1589140NA
      13rs207701130884562–/KATNAL113q12.3231287NA
      9kgp182114275597138ALDH1A1/–9q21.112991370NA
      22rs73928126277148MYO18B/–22q12.114051476NA
      4rs7436952307574ZFYVE28 /–4p1610081087NA
      7kgp2280812479894616–/GNAI17q21.1270352
      • Wang H.
      • Guo M.
      • Shen S.
      • He L.
      • Zhang X.
      • Zuo X.
      • et al.
      Variants in SELL, MRPS36P2, TP63, DDB2, CACNA1H, ADAM19, GNAI1, CDH13 and GABRG2 interact to confer risk of acne in Chinese population.
      3rs92406763644694–/TRNAE27P3p14.132333323NA
      11rs110284623629578–/OR7E117P11p15.4263354NA
      14kgp1186978234233909NPAS3/–14q1397179819NA
      14rs1710683378556038–/FRDAP14q24.327512853NA
      4kgp1045748341022652APBB2/–4p14-p1311941305NA
      4rs1003324841030604APBB2/–4p14-p1311941305NA
      6rs3912161160669718SLC22A2/–6q25.2-26275386NA
      2rs1550068221826031–/EPHA42q35-36293405NA
      10rs474919027115039ABI1/–10p12.124072520NA
      15kgp2004174797880882–/LOC10192728615q26.2752868NA
      16kgp987771013158214SHISA9/–16p13.123042422NA
      11kgp286548043952796–/ALKBH311p11.218662010NA
      10rs709066017580890–/PRPF38AP210p12.317241895NA
      4rs2100695182932198LOC101928703/–4q34-q3554415646NA
      3rs25968903915789LOC101927236/–3q2662606480NA
      8kgp205658312018828MYOM2/–8p23.317772000NA
      2rs6750345134579078–/NCKAP52q21.211061389NA
      11rs94819470424943SHANK2/–11q13.3-13.436644170NA
      6rs4142055152550483SYNE1/–6q25.135854192NA
      7rs51569379893373–/MAGI27q21.181078935NA
      6rs80526431623873APOM/–6p21.3970210778NA
      9rs47409909805134PTPRD/–9p232524326617NA
      Abbreviations: CHR, chromosome; NA, no literature evidence that the gene related to acne or the metabolism of androgen or sebum; SNP, single nucleotide polymorphism.
      Supplementary Table S3Description of single nucleotide polymorphisms in six candidate genes
      GeneChromosomePosition (GRCH37.p13)SNPs
      TP633189304602rs6776964
      TP633189356941rs7636839
      Duplicated single nucleotide polymorphisms in the 0.05% peak signals.
      TP633189359903rs12107025
      TP633189376175rs10937401
      TP633189395680rs13097576
      TP633189407380rs16864723
      TP633189407444rs16864725
      TP633189409196rs2889918
      TP633189409341rs7618742
      TP633189419681rs7647665
      TP633189435816rs10937406
      TP633189452211rs11914582
      TP633189456729rs4686525
      TP633189457674rs6800495
      TP633189484028rs6780467
      TP633189499173rs16864784
      TP633189508471rs9854771
      TP633189522258rs7619549
      TP633189529969rs16864809
      TP633189536660rs9881595
      TP633189539320rs9879356
      TP633189582249rs2276792
      TP633189585208rs6783043
      TP633189586030rs1399773
      TP633189599324rs7613791
      TP633189604160rs1345186
      TP633189631559rs1447931
      F13A166148267rs423021
      F13A166153379rs6937073
      F13A166158149rs381061
      F13A166161313rs9379013
      F13A166161662rs4960172
      F13A166162406rs17141831
      F13A166163088rs6911594
      F13A166163492rs13202850
      F13A166164170rs4960173
      F13A166165468rs434602
      F13A166167621rs435048
      F13A166168194rs900401
      F13A166169656rs7769202
      F13A166173370rs17141840
      F13A166173987rs786735
      F13A166174866rs5982
      F13A166175591rs407447
      F13A166175975rs11969912
      F13A166176580rs7740009
      F13A166176625rs7774391
      F13A166176838rs6597195
      F13A166177044rs3778354
      Single nucleotide polymorphisms could not designed in the chip.
      F13A166178328rs3116567
      Single nucleotide polymorphisms could not designed in the chip.
      F13A166179882rs3778353
      F13A166181526rs3024443
      F13A166182605rs2274393
      F13A166184819rs3799558
      F13A166185017rs3799557
      F13A166199882rs4959374
      F13A166204341rs9392757
      F13A166223294rs3024409
      F13A166226951rs1742928
      F13A166237117rs9504730
      F13A166241281rs1781795
      F13A166242946rs1742924
      F13A166243797rs1742925
      F13A166244124rs1613671
      F13A166249645rs3024388
      F13A166250975rs3024369
      F13A166256833rs7766109
      F13A166260749rs3901123
      F13A166274161rs3851513
      F13A166275932rs9328348
      F13A166280288rs4959377
      F13A166282943rs12664620
      F13A166284125rs9502429
      F13A166289857rs1267914
      F13A166290904rs4960186
      F13A166303211rs3024347
      F13A166304531rs1742932
      F13A166305477rs2295753
      F13A166306405rs714408
      F13A166309698rs1742937
      F13A166311188rs1674045
      F13A166311701rs2755416
      F13A166319379rs3024317
      F13A166322875rs3024304
      F13A166322978rs1267858
      DDB21147226488rs7937101
      DDB21147237359rs4647709
      DDB21147237680rs2291120
      DDB21147243665rs1685404
      DDB21147252237rs4647730
      DDB21147258979rs4647756
      DDB21147260272rs2013867
      DDB21147261260rs11988
      CACNA1H161184967rs11865472
      CACNA1H161192213rs4566170
      CACNA1H161198938rs909910
      CACNA1H161200067rs7184967
      CACNA1H161212523rs11859240
      CACNA1H161225628rs11640796
      CACNA1H161235314rs1075789
      CACNA1H161237356rs7191794
      CACNA1H161239810rs12929353
      CACNA1H161241997rs11248859
      CACNA1H161244201rs8053994
      CACNA1H161246270rs1005454
      CACNA1H161252599rs9924677
      CACNA1H161253529rs2050114
      CACNA1H161261282rs4984637
      CACNA1H161266020rs2738890
      CACNA1H161269003rs3751886
      Duplicated single nucleotide polymorphisms in the 0.05% peak signals.
      CACNA1H161269740rs2745137
      CACNA1H161271348rs8049082
      CACNA1H161272472rs7198064
      CACNA1H161272865rs4984639
      CACNA1H161273638rs909920
      CACNA1H161273803rs909921
      Duplicated single nucleotide polymorphisms in the 0.05% peak signals.
      CACNA1H161273982rs12934797
      CMIP1681486176rs898965
      CMIP1681488372rs13333580
      CMIP1681492311rs9940384
      CMIP1681497498rs17197603
      CMIP1681497707rs2317240
      CMIP1681497952rs898962
      CMIP1681503540rs12596482
      CMIP1681508633rs16955417
      CMIP1681509293rs2927332
      CMIP1681510742rs10493891
      CMIP1681511806rs2966079
      CMIP1681514505rs2927322
      Single nucleotide polymorphisms could not designed in the chip.
      CMIP1681525727rs2926004
      CMIP1681538620rs2966093
      CMIP1681547687rs8182218
      CMIP1681548925rs11862343
      CMIP1681568064rs13333159
      CMIP1681571725rs876673
      CMIP1681579433rs9319570
      CMIP1681579923rs12932885
      CMIP1681595186rs2911276
      CMIP1681596444rs2966120
      Single nucleotide polymorphisms could not designed in the chip.
      CMIP1681597173rs997218
      CMIP1681602212rs12930850
      CMIP1681602370rs2287112
      CMIP1681603619rs12925980
      Single nucleotide polymorphisms could not designed in the chip.
      CMIP1681608669rs4632124
      Single nucleotide polymorphisms could not designed in the chip.
      CMIP1681616721rs8054441
      CMIP1681620003rs16955590
      CMIP1681632769rs6564894
      CMIP1681634863rs9925501
      CMIP1681640182rs7192328
      CMIP1681644493rs16955656
      CMIP1681652322rs12927866
      CMIP1681653488rs7206411
      CMIP1681654451rs16955675
      Single nucleotide polymorphisms could not designed in the chip.
      CMIP1681658664rs7197860
      CMIP1681690091rs4243209
      CMIP1681699087rs3935338
      CMIP1681726584rs11642818
      CMIP1681728192rs4888165
      CMIP1681730809rs7186510
      CMIP1681732256rs765413
      CMIP1681740950rs2052587
      CDH131682655794rs4445897
      CDH131682662268rs4783244
      CDH131682672327rs12922394
      CDH131682680391rs7187680
      CDH131682680526rs17176567
      CDH131682681988rs3844415
      CDH131682687797rs17177428
      CDH131682700502rs12922128
      CDH131682704082rs10451170
      CDH131682705649rs9938576
      CDH131682707348rs9936363
      CDH131682709161rs16958140
      CDH131682710856rs16958148
      CDH131682711504rs17179209
      CDH131682712315rs10514555
      CDH131682719340rs10514556
      CDH131682719836rs8060937
      CDH131682727084rs7342746
      CDH131682752831rs9936126
      CDH131682758427rs13334499
      CDH131682760502rs11150491
      CDH131682768568rs6565063
      CDH131682782542rs898862
      CDH131682782587rs1000078
      CDH131682795213rs8046812
      Single nucleotide polymorphisms could not designed in the chip.
      CDH131682801388rs726122
      CDH131682812366rs8043851
      CDH131682819116rs17192152
      CDH131682821028rs12933198
      CDH131682822631rs1870849
      CDH131682828365rs12929663
      CDH131682829401rs4783277
      CDH131682832949rs4598906
      CDH131682833827rs11860282
      CDH131682836706rs2199430
      Single nucleotide polymorphisms could not designed in the chip.
      CDH131682843167rs9319574
      CDH131682846781rs9889056
      CDH131682855053rs1381504
      CDH131682856013rs2549161
      CDH131682863283rs1903623
      CDH131682864912rs7498941
      CDH131682865227rs1155970
      Single nucleotide polymorphisms could not designed in the chip.
      CDH131682865479rs1155972
      CDH131682869552rs2549138
      CDH131682871769rs2061628
      CDH131682872628rs7206608
      CDH131682872778rs9934819
      CDH131682887312rs286676
      CDH131682891561rs17673125
      CDH131682893311rs12597819
      CDH131682900876rs7206473
      CDH131682900986rs11150505
      CDH131682912374rs17674039
      CDH131682916682rs2059230
      CDH131682918371rs1559310
      CDH131682921977rs12598386
      CDH131682923394rs11150513
      CDH131682923788rs9937259
      CDH131682935671rs17674675
      CDH131682945551rs7199677
      CDH131682949088rs17675094
      CDH131682974628rs918655
      CDH131682977849rs7190176
      CDH131682987872rs11639621
      CDH131682992829rs11861198
      CDH131683001098rs8064211
      CDH131683005708rs1108698
      CDH131683008879rs13313558
      CDH131683018900rs16959010
      CDH131683019747rs10492869
      CDH131683042192rs9939677
      Single nucleotide polymorphisms could not designed in the chip.
      CDH131683042938rs7203988
      CDH131683065491rs7189859
      CDH131683069709rs4473177
      CDH131683071146rs11150533
      Single nucleotide polymorphisms could not designed in the chip.
      CDH131683072103rs8053971
      CDH131683076634rs4783307
      CDH131683077536rs4783309
      CDH131683084290rs6565107
      Single nucleotide polymorphisms could not designed in the chip.
      CDH131683086966rs11150535
      CDH131683104055rs8058531
      CDH131683105745rs11864653
      CDH131683111996rs7499448
      CDH131683120610rs6565116
      CDH131683122828rs12920161
      CDH131683128048rs12928063
      CDH131683138833rs12929782
      Single nucleotide polymorphisms could not designed in the chip.
      CDH131683141106rs17194225
      CDH131683144850rs7196583
      CDH131683146684rs9930312
      CDH131683152847rs11863669
      CDH131683164216rs12102847
      CDH131683165195rs7194173
      CDH131683175556rs9927840
      CDH131683175687rs12597394
      CDH131683179357rs6565137
      CDH131683181462rs8064200
      CDH131683188272rs7203576
      CDH131683188957rs13339361
      CDH131683196443rs4341727
      CDH131683211524rs4238732
      CDH131683214480rs7188594
      CDH131683219101rs9931447
      CDH131683221185rs9921224
      CDH131683225719rs12448939
      CDH131683232027rs6565151
      CDH131683242605rs4454960
      CDH131683267198rs6565156
      Single nucleotide polymorphisms could not designed in the chip.
      CDH131683281707rs8056448
      CDH131683289483rs8053104
      CDH131683290017rs17756260
      CDH131683294053rs7198542
      CDH131683302025rs16960036
      CDH131683304743rs17679225
      CDH131683305223rs12444181
      CDH131683310923rs1559439
      CDH131683318740rs882597
      CDH131683319882rs17195894
      CDH131683328162rs2875784
      CDH131683330610rs1424189
      CDH131683342234rs723919
      CDH131683342389rs723920
      CDH131683367122rs1364298
      CDH131683375258rs17211336
      CDH131683384666rs11861609
      Single nucleotide polymorphisms could not designed in the chip.
      CDH131683390637rs1544812
      CDH131683391288rs9938206
      CDH131683405311rs4782782
      CDH131683418974rs889712
      CDH131683421181rs9319441
      CDH131683423535rs8052595
      CDH131683430201rs3736239
      CDH131683441402rs17213769
      CDH131683446147rs12599334
      CDH131683450822rs1424183
      CDH131683451961rs9674268
      CDH131683462459rs4782789
      Single nucleotide polymorphisms could not designed in the chip.
      CDH131683462605rs4782791
      CDH131683470269rs12148952
      CDH131683472854rs12929721
      CDH131683474471rs720202
      CDH131683487316rs8054845
      CDH131683490774rs11646484
      CDH131683518977rs7206140
      CDH131683526056rs2130157
      CDH131683551296rs4514666
      CDH131683553443rs4444330
      CDH131683554140rs9923206
      CDH131683566029rs7190681
      CDH131683569787rs4782814
      CDH131683583925rs12921461
      CDH131683585376rs8061801
      CDH131683596353rs4401039
      CDH131683598853rs12918351
      CDH131683600397rs7201194
      CDH131683615732rs8054307
      CDH131683615856rs8054505
      CDH131683617578rs11149581
      CDH131683621073rs12923174
      Single nucleotide polymorphisms could not designed in the chip.
      CDH131683621967rs7200573
      Single nucleotide polymorphisms could not designed in the chip.
      CDH131683630444rs747233
      CDH131683636801rs1833965
      CDH131683638982rs8055119
      CDH131683648676rs9938720
      CDH131683658886rs6563953
      CDH131683661466rs11862535
      CDH131683665234rs12449138
      CDH131683681953rs13337331
      CDH131683685999rs7203252
      CDH131683687645rs8051748
      CDH131683705819rs1017234
      Single nucleotide polymorphisms could not designed in the chip.
      CDH131683711369rs11149599
      CDH131683724892rs6563969
      CDH131683736070rs9940922
      CDH131683737951rs13380527
      CDH131683740126rs1364120
      CDH131683741730rs7190410
      CDH131683742045rs377797
      Single nucleotide polymorphisms could not designed in the chip.
      CDH131683743546rs368774
      CDH131683747327rs375142
      CDH131683750473rs8051258
      CDH131683751523rs17770142
      CDH131683756238rs4782554
      CDH131683756819rs9929756
      Single nucleotide polymorphisms could not designed in the chip.
      CDH131683764215rs446490
      CDH131683765357rs16961506
      CDH131683770853rs401443
      CDH131683777112rs17699108
      CDH131683777938rs3784985
      CDH131683779219rs366556
      CDH131683783490rs1645844
      CDH131683785148rs11641114
      CDH131683785312rs734021
      CDH131683785759rs10514597
      CDH131683793018rs7203154
      CDH131683799581rs889494
      CDH131683799720rs889492
      CDH131683805141rs10514598
      CDH131683809917rs7198623
      CDH131683814858rs16961746
      CDH131683819899rs692612
      CDH131683822338rs16961799
      CDH131683822637rs16961807
      CDH131683824498rs463480
      CDH131683827801rs2326025
      CDH131683828453rs464557
      CDH131683831763rs9928133
      CDH131683839295rs8056042
      1 Duplicated single nucleotide polymorphisms in the 0.05% peak signals.
      2 Single nucleotide polymorphisms could not designed in the chip.
      Supplementary Table S4Association results for 159 single nucleotide polymorphisms in six candidate genes in replication stage
      CHRSNPsPosition (GRCH37.p13)CHISQP-ValueOR95% CIFDR
      LowerUpper
      3rs98815951895366600.0089.28E-011.0040.9161.1010.999
      3rs98547711895084710.0119.18E-011.0070.8831.1480.999
      3rs168648091895299690.0149.06E-011.0060.9081.1150.999
      3rs76195491895222580.117.40E-011.020.9061.1490.999
      3rs13997731895860300.3925.31E-011.0310.9381.1330.999
      3rs98793561895393200.4854.86E-011.0330.9431.1310.999
      3rs68004951894576740.5084.76E-010.9620.8641.0710.999
      3rs76187421894093410.6914.06E-010.9270.7761.1080.999
      3rs28899181894091961.3652.43E-011.0630.961.1770.999
      3rs168647251894074441.8651.72E-011.1210.9521.320.999
      3rs130975761893956801.9551.62E-011.0670.9741.1680.999
      6rs900401616819409.98E-0110.9141.0940.999
      6rs6911594616308809.96E-0110.9031.1060.999
      6rs12664620628294309.85E-011.0010.8841.1330.999
      6rs932834862759320.0029.60E-011.0030.9091.1060.999
      6rs302438862496450.0029.60E-011.0020.9141.0990.999
      6rs71440863064050.0059.43E-010.9970.9111.0910.999
      6rs227439361826050.0079.35E-011.0040.9171.0990.999
      6rs390112362607490.0119.17E-010.9940.8931.1070.999
      6rs379955861848190.028.88E-011.0080.9071.1190.999
      6rs950242962841250.0368.49E-011.0090.9211.1050.999
      6rs385151362741610.0478.29E-011.0130.9021.1380.999
      6rs1196991261759750.0797.79E-011.0150.9161.1250.999
      6rs40744761755910.087.77E-010.9860.8921.0890.999
      6rs302430463228750.1227.27E-011.0160.9281.1130.999
      6rs1320285061634920.1367.12E-011.0240.9031.1610.999
      6rs174293263045310.1766.75E-010.9750.8651.0990.999
      6rs1714184061733700.1856.67E-010.9760.8741.090.999
      6rs379955761850170.1876.65E-011.0240.9211.1380.999
      6rs174292562437970.2646.07E-010.9720.871.0850.999
      6rs78673561739870.3515.54E-011.0520.8891.2440.999
      6rs777439161766250.3545.52E-010.9730.8881.0660.999
      6rs126791462898570.4644.96E-010.9690.8841.0620.999
      6rs38106161581490.5034.78E-011.0330.9441.1310.999
      6rs776920261696560.5264.68E-010.9610.8641.070.999
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      6rs598261748660.6354.25E-011.0420.9421.1520.999
      6rs939275762043410.6394.24E-010.9630.8791.0560.999
      6rs302444361815260.7113.99E-011.040.951.1380.999
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      6rs167404563111880.8753.50E-011.0730.9261.2450.999
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      6rs126785863229781.3122.52E-011.0570.9611.1640.999
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      6rs377835361798821.9121.67E-010.9180.8121.0370.999
      6rs659719561768382.3131.28E-011.0730.981.1750.995
      6rs1714183161624062.4511.17E-010.8980.7851.0280.991
      6rs229575363054772.9448.62E-020.920.8371.0120.853
      6rs435048616762114.331.54E-041.3711.1641.6160.022
      11rs11988472612601.2252.68E-011.1620.891.5170.999
      11rs2291120472376806.1541.31E-021.3231.061.6520.289
      16rs20616288287176909.94E-011.0010.7751.2930.999
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      16rs7187680826803910.0737.88E-011.0140.9161.1230.999
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      16rs107578912353140.1976.57E-010.9790.8921.0750.999
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      16rs3844415826819881.0053.16E-011.0490.9561.1510.999
      16rs8058531831040551.013.15E-010.9420.8381.0590.999
      16rs1164079612256281.0353.09E-010.9510.8631.0480.999
      16rs4341727831964431.2042.73E-011.0830.9391.2490.999
      16rs8043851828123661.2282.68E-011.060.9561.1750.999
      16rs2966079815118061.2582.62E-010.940.8431.0470.999
      16rs898962814979521.2672.60E-010.9410.8451.0470.999
      16rs17770142837515231.2842.57E-010.8670.6781.110.999
      16rs4598906828329491.3372.48E-011.0630.9581.180.999
      16rs17673125828915611.3612.43E-010.8860.7231.0860.999
      16rs8055119836389821.4512.28E-010.9240.8131.0510.999
      16rs2287112816023701.5562.12E-010.9150.7951.0520.999
      16rs16958148827108561.5792.09E-010.9360.8451.0380.999
      16rs2317240814977071.6032.06E-011.060.9691.1610.999
      16rs1870849828226311.6182.03E-011.1920.9091.5630.999
      16rs13339361831889571.7991.80E-010.9290.8341.0350.999
      16rs17176567826805261.8761.71E-011.1060.9581.2770.999
      16rs446490837642152.0261.55E-011.0740.9731.1860.999
      16rs11861198829928292.0651.51E-011.2360.9261.6490.999
      16rs12597819828933112.2621.33E-010.9230.8321.0250.999
      16rs17674039829123742.3391.26E-010.8060.6121.0630.995
      16rs11864653831057452.3851.23E-011.0960.9761.2310.995
      16rs10514597837857592.6071.06E-011.1150.9771.2730.991
      16rs882597833187403.6555.59E-021.0980.9981.2080.642
      16rs9319570815794334.1074.27E-021.2561.0071.5660.573
      16rs4782814835697874.4063.58E-021.1031.0071.2090.535
      16rs17674675829356714.7412.95E-021.2361.0211.4960.497
      16rs8054845834873164.8622.75E-020.8780.7830.9860.493
      16rs17195894833198827.6635.64E-031.21.0551.3660.147
      16rs11086988300570810.631.11E-031.4051.1441.7250.046
      16rs80564488328170710.979.28E-041.541.191.9920.044
      16rs71985428329405312.643.79E-040.8420.7660.9260.027
      Abbreviations: CHISQ, chi-square-based Cochran's Q statistic; CHR, chromosome; CI, confidence interval; FDR, false discovery rate; OR, odds ratio; SNP, single nucleotide polymorphism.

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