Abstract
There is growing evidence of shared risk alleles for complex traits (pleiotropy), including autoimmune and neuropsychiatric diseases. This might be due to sharing among all individuals (whole-group pleiotropy) or a subset of individuals in a genetically heterogeneous cohort (subgroup heterogeneity). Here we describe the use of a well-powered statistic, BUHMBOX, to distinguish between those two situations using genotype data. We observed a shared genetic basis for 11 autoimmune diseases and type 1 diabetes (T1D; P < 1 × 10−4) and for 11 autoimmune diseases and rheumatoid arthritis (RA; P < 1 × 10−3). This sharing was not explained by subgroup heterogeneity (corrected PBUHMBOX > 0.2; 6,670 T1D cases and 7,279 RA cases). Genetic sharing between seronegative and seropostive RA (P < 1 × 10−9) had significant evidence of subgroup heterogeneity, suggesting a subgroup of seropositive-like cases within seronegative cases (PBUHMBOX = 0.008; 2,406 seronegative RA cases). We also observed a shared genetic basis for major depressive disorder (MDD) and schizophrenia (P < 1 × 10−4) that was not explained by subgroup heterogeneity (PBUHMBOX = 0.28; 9,238 MDD cases).
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Acknowledgements
This work was supported in part by funding from the US National Institutes of Health (NIH) (1R01AR063759 (S.R.), 1R01AR062886 (S.R.), 1UH2AR067677-01 (S.R.), and U19AI111224-01 (S.R.)) and Doris Duke Charitable Foundation grant 2013097. B.H. is supported by the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea (2016-0717) and the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI14C1731). J.G.P. is supported by Fulbright Canada, the Weston Foundation, and Brain Canada through the Canada Brain Research Fund. K.S. is supported by an NIH training grant (T32HG002295). N.R.W. is supported by the Australian National Health and Medical Research Council (1087889 and 1078901). This research uses resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by grant U01DK062418.
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B.H. and S.R. conceived the statistical approach and organized the project. B.H., J.G.P., and S.R. led and coordinated analyses and wrote the initial manuscript. E.S. and N.R.W. provided guidance on the statistical approach. K.S., C.H.L., D.D., X.H., Y.R.P., and E.K. contributed to the implementation of specific analyses and offered feedback on the statistical methodologies. P.K.G., S.R.D., J.W., J.M., S.E., L.K., S.R., and T.H. contributed RA samples and insight on the clinical implications to RA. W.-M.C., S.O.-G., and S.S.R. contributed T1D samples and insight on clinical implications to T1D. The Major Depressive Disorder Working Group contributed MDD samples and insight on the clinical implications to MDD. All authors contributed to the final manuscript.
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Supplementary Figure 1 Power and false positive rate of the BUHMBOX and GRS approaches for different situations.
Under true pleiotropy without subgroup heterogeneity, the GRS approach appropriately demonstrated 64.8% power to detect shared genetic structure and BUHMBOX demonstrated an appropriate false positive rate of 4.3%. Under true subgroup heterogeneity without pleiotropy, the GRS approach demonstrated 100% power to detect shared genetic structure and BUHMBOX demonstrated 81.7% power to detect subgroup heterogeneity at α = 0.05. The GRS approach has power for both situations and therefore cannot distinguish subgroup heterogeneity from pleiotropy.
Supplementary Figure 2 Expected correlations with respect to heterogeneity proportion, risk allele frequencies, and odds ratios.
The plots show the expected correlations between pairs of alleles for different risk allele frequencies (RAFs) and odds ratios (ORs). (a) We assumed OR = 1.5 for both alleles. (b) We assumed RAF = 0.5 for both alleles.
Supplementary Figure 3 Power of BUHMBOX as a function of effect size.
This plot shows the power of BUHMBOX for detecting heterogeneity in terms of the mean effect size and the proportion of samples that comprise a hidden subgroup (heterogeneity proportion, π). We assume that we have 2,000 cases, 2,000 controls, and 50 associated loci. We sampled OR and RAF values from the GWAS catalog and scaled all log-transformed OR values to have a desired mean value. White lines denote 20%, 40%, 60%, and 80% power.
Supplementary Figure 4 Power of BUHMBOX in polygenic modeling.
We simulated GWAS and examined the power of BUHMBOX by including moderately significant loci up to P < 0.01. We modeled the genetic architecture of disease using rheumatoid arthritis, on the basis of results from Stahl et al. (Nat. Genet. 44, 483–489, 2012). To simulate 2,231 causal variants, we combined 71 independent known rheumatoid arthritis risk loci with an additional 2,160 loci sampled from the joint posterior distribution of RAF and OR values presented in Stahl et al. For null loci, we also used the null RAF distribution presented in Stahl et al. Given this disease model, we simulated a GWAS with 3,964 cases and 12,052 controls (sample sizes from Stahl et al.), assuming disease prevalence of 0.01. Given these GWAS results, we used only the top k GWAS loci defined by P-value threshold t and their observed OR estimates for BUHMBOX power simulations. We assumed N = 5,000 and π = 0.5 for power evaluation and tried different P-value thresholds t from 5 × 10−8 to 0.01.
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Supplementary Text and Figures
Supplementary Figures 1–4, Supplementary Tables 1, 2, 5 and 6, and Supplementary Note. (PDF 4068 kb)
Supplementary Table 3
Detailed SNP information used for GRS and BUHMBOX analyses. (XLSX 136 kb)
Supplementary Table 4
GRS and BUHMBOX results. (XLSX 54 kb)
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Han, B., Pouget, J., Slowikowski, K. et al. A method to decipher pleiotropy by detecting underlying heterogeneity driven by hidden subgroups applied to autoimmune and neuropsychiatric diseases. Nat Genet 48, 803–810 (2016). https://doi.org/10.1038/ng.3572
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DOI: https://doi.org/10.1038/ng.3572
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