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A Transethnic Mendelian Randomization Study Identifies Causality of Obesity on Risk of Psoriasis

Open AccessPublished:December 05, 2018DOI:https://doi.org/10.1016/j.jid.2018.11.023

      Abbreviations:

      BMI (body mass index), GWAS (genome-wide association study), IVW (inverse variance-weighted), MR (Mendelian randomization), SNP (single nucleotide polymorphism)
      To the Editor
      Psoriasis is a chronic disorder characterized by cutaneous and systemic manifestations. Epidemiological studies have reported increased comorbidity of psoriasis with numerous complex diseases such as metabolic clinical measurements (
      • Greb J.E.
      • Goldminz A.M.
      • Elder J.T.
      • Lebwohl M.G.
      • Gladman D.D.
      • Wu J.J.
      • et al.
      Psoriasis.
      ,
      • Naito R.
      • Imafuku S.
      Distinguishing features of body mass index and psoriasis in men and women in Japan: a hospital-based case-control study.
      ). However, interpretation of the comorbidity remains controversial to date, because causal inference between correlated phenotypes is difficult when depending solely on epidemiological studies. Identification of causal inference between correlated phenotypes has significant clinical impacts, because modification of the causal phenotypes could benefit treatment of the outcome phenotypes. Drugs indicated by the causal phenotypes could also be promising targets of drug repositioning for the outcome phenotypes (
      • Holmes M.V.
      • Ala-Korpela M.
      • Smith G.D.
      Mendelian randomization in cardiometabolic disease: challenges in evaluating causality.
      ). Therefore, alternative approaches to strengthen causal inference on psoriasis are warranted.
      An approach becoming popular for this purpose is use of genetic data (
      • Pingault J.B.
      • O’Reilly P.F.
      • Schoeler T.
      • Ploubidis G.B.
      • Rijsdijk F.
      • Dudbridge F.
      Using genetic data to strengthen causal inference in observational research.
      ). Genetically determined phenotype profiles are robust to confounding factors acquired during a lifetime, which could be interpreted as ideal randomization of subjects. Mendelian randomization (MR) is an approach to infer causal inference between phenotypes using the genome-wide association study (GWAS) results (
      • Holmes M.V.
      • Ala-Korpela M.
      • Smith G.D.
      Mendelian randomization in cardiometabolic disease: challenges in evaluating causality.
      ,
      • Hemani G.
      • Zheng J.
      • Elsworth B.
      • Wade K.H.
      • Haberland V.
      • Baird D.
      • et al.
      The MR-Base platform supports systematic causal inference across the human phenome.
      ). Because of (i) achievement of large-scale GWASs of a variety of human phenotypes with public data deposit and (ii) development of MR analytical methods that robustly infer causality, such as MR-Egger (
      • Burgess S.
      • Thompson S.G.
      Interpreting findings from Mendelian randomization using the MR-Egger method.
      ), MR is now one of the best approaches to infer causality. Generally, the largest available GWAS result within a single ancestry is used for an MR analysis to afford robust conclusions. Thus, confirmation of the MR analysis results requires additional validation using GWAS with independent ancestry.
      Here, we conducted a transethnic MR analysis to estimate causal inference on psoriasis. We obtained the genome-wide summary statistics of the previously reported psoriasis GWAS of European populations (13,229 case and 21,543 control individuals) (
      • Tsoi L.C.
      • Stuart P.E.
      • Tian C.
      • Gudjonsson J.E.
      • Das S.
      • Zawistowski M.
      • et al.
      Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants.
      ) and Japanese population (282 case and 426 control individuals) (
      • Hirata J.
      • Hirota T.
      • Ozeki T.
      • Kanai M.
      • Sudo T.
      • Tanaka T.
      • et al.
      Variants at HLA-A, HLA-C, and HLA-DQB1 confer risk of psoriasis vulgaris in Japanese.
      ) (see Supplementary Table S1 online). Both of the psoriasis GWASs were conducted by applying whole-genome sequencing–based genotype imputation, which yielded high coverage of the genome-wide variants suitable for the MR analysis (>6,000,000 variants). As for the European GWAS, the participants in the cohort collected by 23andMe (Mountain View, CA) were excluded because of their policies on summary data sharing. We thus reconducted the GWAS meta-analysis after sample exclusion for our MR analyses. We admit that the sample size of the Japanese GWAS was relatively smaller, which warrants further accumulation of participants.
      We focused on metabolic clinical measurements as exposure phenotypes, for which the large-scale GWAS results have been released in both populations. We selected nine measurements: obesity (body mass index [BMI]); levels of triglycerides, total cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, blood sugar, and hemoglobin A1c; and systolic and diastolic blood pressure (on average 149,958 subjects per trait) (see Supplementary Table S2 online) (
      • Akiyama M.
      • Okada Y.
      • Kanai M.
      • Takahashi A.
      • Momozawa Y.
      • Ikeda M.
      • et al.
      Genome-wide association study identifies 112 new loci for body mass index in the Japanese population.
      ,
      • Ehret G.B.
      • Munroe P.B.
      • Rice K.M.
      • Bochud M.
      • Johnson A.D.
      • Chasman D.I.
      • et al.
      Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.
      ,
      • Kanai M.
      • Akiyama M.
      • Takahashi A.
      • Matoba N.
      • Momozawa Y.
      • Ikeda M.
      • et al.
      Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases.
      ,
      • Locke A.E.
      • Kahali B.
      • Berndt S.I.
      • Justice A.E.
      • Pers T.H.
      • Day F.R.
      • et al.
      Genetic studies of body mass index yield new insights for obesity biology.
      ,
      • Scott R.A.
      • Lagou V.
      • Welch R.P.
      • Wheeler E.
      • Montasser M.E.
      • Luan J.
      • et al.
      Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.
      ,
      • Wheeler E.
      • Leong A.
      • Liu C.T.
      • Hivert M.F.
      • Strawbridge R.J.
      • Podmore C.
      • et al.
      Impact of common genetic determinants of hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: a transethnic genome-wide meta-analysis.
      ,
      • Willer C.J.
      • Schmidt E.M.
      • Sengupta S.
      • Peloso G.M.
      • Gustafsson S.
      • Kanoni S.
      • et al.
      Discovery and refinement of loci associated with lipid levels.
      ). After selection of the lead variants (or the proxy single nucleotide polymorphisms [SNPs] in linkage disequilibrium of r2 ≥ 0.5 in the corresponding 1000 Genomes Project phase1v3 populations) at the loci with genome-wide significance threshold (P < 5.0 × 10–8) and exclusion of the highly pleiotropic locus of the major histocompatibility complex region, on average 41.3 loci per trait were obtained.
      We adopted two-sample MR, one of the MR analysis approaches that handles summary statistics obtained from separate studies. In addition to the typical method of inverse variance weighted (IVW), we adopted MR analysis based on Egger regression (i.e., MR-Egger), which is statistically less powerful but more robust to bias caused by directional pleiotropy (
      • Burgess S.
      • Thompson S.G.
      Interpreting findings from Mendelian randomization using the MR-Egger method.
      ). We used the MR-Base platform implemented as a package of R statistical software (R Core Development Team, Vienna, Austria) (
      • Hemani G.
      • Zheng J.
      • Elsworth B.
      • Wade K.H.
      • Haberland V.
      • Baird D.
      • et al.
      The MR-Base platform supports systematic causal inference across the human phenome.
      ).
      For Europeans, significant causality of genetically increased BMI on risk of psoriasis was estimated (β = 0.464 and P = 3.1 × 10–5 in IVW, and β = 0.697 and P = 0.0093 in MR-Egger) (Table 1 and Figure 1). For Japanese, significant causality of BMI on psoriasis risk was also observed in the IVW analysis with a concordant directional effect (β = 1.275 and P = 0.0069). Although the MR-Egger result was not significant (β = 1.499 and P = 0.27), the effect size estimate was larger than that of IVW. Because phenotype normalization methods were different among the original GWAS, direct comparison of the estimated causal effect sizes of the BMI-associated SNPs on psoriasis between the studies was difficult. We assessed potential bias in the results of MR analyses, mostly caused by SNP pleiotropy, by applying a set of sensitivity analyses including heterogeneity test, leave-one-out analysis, and funnel plots implemented in the MR-Base platform, but we did not find existence of apparent bias (see Supplementary Figure S1 online). We applied the reverse MR analysis inferring causality of psoriasis on BMI, but we did not observe significant causality (P > 0.75) (see Supplementary Figure S2 online).
      Table 1Results of the transethnic MR analyses inferring causality of the clinical metabolic measurements on psoriasis
      TraitMR MethodMR Result in EuropeansMR Result in JapaneseMeta-Analysis
      Beta (SE)PBeta (SE)PP
      Body mass indexInverse variance weighted0.464 (0.112)3.1×10-51.275 (0.472)0.00691.2 × 10–6
      MR-Egger0.697 (0.262)0.00931.499 (1.342)0.270.0088
      TriglycerideInverse variance weighted0.085 (0.088)0.330.139 (0.369)0.710.34
      MR-Egger–0.064 (0.129)0.620.748 (0.561)0.190.56
      Total cholesterolInverse variance weighted0.054 (0.063)0.39–0.595 (0.476)0.210.78
      MR-Egger0.126 (0.115)0.28–0.663 (0.900)0.470.80
      HDL cholesterolInverse variance weighted–0.026 (0.072)0.720.190 (0.318)0.550.87
      MR-Egger0.024 (0.109)0.82–0.048 (0.509)0.930.92
      LDL cholesterolInverse variance weighted0.051 (0.054)0.35–0.300 (0.385)0.440.91
      MR-Egger0.180 (0.088)0.046–0.134 (0.535)0.800.22
      Blood sugarInverse variance weighted–0.537 (0.269)0.0460.235 (0.671)0.730.24
      MR-Egger–0.685 (0.943)0.471.940 (2.550)0.460.99
      HbA1cInverse variance weighted–0.143 (0.273)0.60–0.289 (0.417)0.490.39
      MR-Egger0.064 (0.552)0.911.811 (1.661)0.290.41
      Systolic blood pressureInverse variance weighted0.006 (0.010)0.541.080 (0.781)0.170.16
      MR-Egger0.048 (0.033)0.163.818 (2.823)0.190.055
      Diastolic blood pressureInverse variance weighted0.017 (0.017)0.311.010 (0.963)0.290.14
      MR-Egger0.099 (0.058)0.101.560 (3.043)0.620.13
      Abbreviations: HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MR, Mendelian randomization; SE, standard error.
      Figure thumbnail gr1
      Figure 1Regression plots of the BMI-associated variants on psoriasis risk. Dots represent the BMI-associated SNPs plotted along with effect size estimates on BMI (x-axis) and psoriasis risk (y-axis) with 95% confidence intervals in (a) the European populations and (b) the Japanese population. Regression lines obtained from the MR analyses are plotted in red (by IVW) and blue (by MR-Egger). BMI, body mass index; IVW, inverse variance weighted; MR, Mendelian randomization; SNP, single nucleotide polymorphism.
      We then conducted a transethnic meta-analysis of the MR results, using weighted summation of z-scores considering directional concordance of the causal effect estimates. As expected, significant causality of BMI on risk of psoriasis was observed (P = 1.2×10-6 in IVW, and P = 0.0088 in MR-Egger). Although suggestive relationships of LDL cholesterol and blood sugar were observed in Europeans (P < 0.05 in IVW or MR-Egger), these associations were not replicated in Japanese, and transethnic MR analyses did not indicate significant causality of these traits (P > 0.22).
      By using large-scale GWAS results of psoriasis in European and Japanese populations, our transethnic MR analyses identified a causal link for obesity on risk of psoriasis. This study has value as one of the initial successful examples of transethnic MR analysis. Epidemiological studies have pointed to a link between higher BMI and increased incidence or severity of psoriasis (
      • Greb J.E.
      • Goldminz A.M.
      • Elder J.T.
      • Lebwohl M.G.
      • Gladman D.D.
      • Wu J.J.
      • et al.
      Psoriasis.
      ,
      • Naito R.
      • Imafuku S.
      Distinguishing features of body mass index and psoriasis in men and women in Japan: a hospital-based case-control study.
      ), with which our MR analysis results were concordant. Moreover, because our study validated causality (i.e., directional link) of obesity on psoriasis, interventional improvement of obesity itself could be a promising treatment strategy toward better management of psoriasis. Further application of the MR analysis of psoriasis to a wider range of phenotypes, as well as validations in additional ethnicities, is warranted.

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      YO was supported by the Japan Society for the Promotion of Science , KAKENHI ( 15H05670 ,  15H05911 , 15K14429 ), AMED ( 18gm6010001h0003 and 18ek0410041h0002 ), and Takeda Science Foundation . This study was supported by the Bioinformatics Initiative of Osaka University Graduate School of Medicine and the Integrated Frontier Research for Medical Science Division , Institute for Open and Transdisciplinary Research Initiatives , Osaka University .

      Supplementary Material

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