A method to decipher pleiotropy by detecting underlying heterogeneity driven by hidden subgroups applied to autoimmune and neuropsychiatric diseases
Buhm Han, Jennie G Pouget, Kamil Slowikowski, Eli Stahl, Cue Hyunkyu Lee, Dorothee Diogo, Xinli Hu, Yu Rang Park, Eunji Kim, Peter K Gregersen, Solbritt Rantapää Dahlqvist, Jane Worthington, Javier Martin, Steve Eyre, Lars Klareskog, Tom Huizinga, Wei-Min Chen, Suna Onengut-Gumuscu, Stephen S Rich, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Naomi R Wray, Soumya Raychaudhuri, Buhm Han, Jennie G Pouget, Kamil Slowikowski, Eli Stahl, Cue Hyunkyu Lee, Dorothee Diogo, Xinli Hu, Yu Rang Park, Eunji Kim, Peter K Gregersen, Solbritt Rantapää Dahlqvist, Jane Worthington, Javier Martin, Steve Eyre, Lars Klareskog, Tom Huizinga, Wei-Min Chen, Suna Onengut-Gumuscu, Stephen S Rich, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Naomi R Wray, Soumya Raychaudhuri
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).
Conflict of interest statement
The authors declare no competing financial interests.
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References
- Sivakumaran S, et al. Abundant pleiotropy in human complex diseases and traits. Am J Hum Genet. 2011;89:607–618.
- Cotsapas C, et al. Pervasive sharing of genetic effects in autoimmune disease. PLoS Genet. 2011;7:e1002254.
- Cross-Disorder Group of the Psychiatric Genomics Consortium. Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet. 2013;381:1371–1379.
- Fortune MD, et al. Statistical colocalization of genetic risk variants for related autoimmune diseases in the context of common controls. Nat Genet. 2015;47:839–846.
- Lee SH, Yang J, Goddard ME, Visscher PM, Wray NR. Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood. Bioinformatics. 2012;28:2540–2542.
- Cross-Disorder Group of the Psychiatric Genomics Consortium. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet. 2013;45:984–994.
- Bulik-Sullivan B, et al. An atlas of genetic correlations across human diseases and traits. Nat Genet. 2015;47:1236–1241.
- Pendergrass SA, et al. Phenome-wide association study (PheWAS) for detection of pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network. PLoS Genet. 2013;9:e1003087.
- Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015;372:793–795.
- Criswell LA, et al. Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet. 2005;76:561–571.
- Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ. Major depression and generalized anxiety disorder. Same genes, (partly) different environments? Arch Gen Psychiatry. 1992;49:716–722.
- Wray NR, Goddard ME, Visscher PM. Prediction of individual genetic risk to disease from genome-wide association studies. Genome Res. 2007;17:1520–1528.
- Purcell SM, et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature. 2009;460:748–752.
- Lee SH, et al. New data and an old puzzle: the negative association between schizophrenia and rheumatoid arthritis. Int J Epidemiol. 2015;44:1706–21.
- Power RA, et al. Polygenic risk scores for schizophrenia and bipolar disorder predict creativity. Nat Neurosci. 2015;18:953–955.
- Solovieff N, Cotsapas C, Lee PH, Purcell SM, Smoller JW. Pleiotropy in complex traits: challenges and strategies. Nat Rev Genet. 2013;14:483–495.
- Wray NR, Lee SH, Kendler KS. Impact of diagnostic misclassification on estimation of genetic correlations using genome-wide genotypes. Eur J Hum Genet. 2012;20:668–674.
- Silverberg MS, et al. Diagnostic misclassification reduces the ability to detect linkage in inflammatory bowel disease genetic studies. Gut. 2001;49:773–776.
- van der Linden MP, et al. Value of anti-modified citrullinated vimentin and third-generation anti-cyclic citrullinated peptide compared with second-generation anti-cyclic citrullinated peptide and rheumatoid factor in predicting disease outcome in undifferentiated arthritis and rheumatoid arthritis. Arthritis Rheum. 2009;60:2232–2241.
- Wiik AS, van Venrooij WJ, Pruijn GJ. All you wanted to know about anti-CCP but were afraid to ask. Autoimmun Rev. 2010;10:90–93.
- Bromet EJ, et al. Diagnostic shifts during the decade following first admission for psychosis. Am J Psychiatry. 2011;168:1186–1194.
- Gibson P, et al. Subtypes of medulloblastoma have distinct developmental origins. Nature. 2010;468:1095–1099.
- Smoller JW, Lunetta KL, Robins J. Implications of comorbidity and ascertainment bias for identifying disease genes. Am J Med Genet. 2000;96:817–822.
- Burrell RA, McGranahan N, Bartek J, Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature. 2013;501:338–345.
- Jeste SS, Geschwind DH. Disentangling the heterogeneity of autism spectrum disorder through genetic findings. Nat Rev Neurol. 2014;10:74–81.
- Flint J, Kendler KS. The genetics of major depression. Neuron. 2014;81:484–503.
- Cho JH, Feldman M. Heterogeneity of autoimmune diseases: pathophysiologic insights from genetics and implications for new therapies. Nat Med. 2015;21:730–738.
- Welter D, et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2014;42:D1001–6.
- Raychaudhuri S, et al. Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk. Nat Genet. 2009;41:1313–1318.
- Eyre S, et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat Genet. 2012;44:1336–1340.
- The International HapMap Consortium. The International HapMap Project. Nature. 2003;426:789–796.
- Smyth DJ, et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med. 2008;359:2767–2777.
- Festen EA, et al. A meta-analysis of genome-wide association scans identifies IL18RAP, PTPN2, TAGAP, and PUS10 as shared risk loci for Crohn’s disease and celiac disease. PLoS Genet. 2011;7:e1001283.
- Zhernakova A, et al. Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci. PLoS Genet. 2011;7:e1002004.
- Jostins L, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491:119–124.
- Cotsapas C, Hafler DA. Immune-mediated disease genetics: the shared basis of pathogenesis. Trends Immunol. 2013;34:22–26.
- Onengut-Gumuscu S, et al. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat Genet. 2015;47:381–386.
- Han B, et al. Fine mapping seronegative and seropositive rheumatoid arthritis to shared and distinct HLA alleles by adjusting for the effects of heterogeneity. Am J Hum Genet. 2014;94:522–532.
- Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–427.
- Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium. A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry. 2013;18:497–511.
- Wray NR, Maier R. Genetic basis of complex genetic disease: The contribution of disease heterogeneity to missing heritability. Curr Epidemiol Rep. 2014;1:220–227.
- Jennrich RI. An asymptotic χ2 test for the equality of two correlation matrices. J Am Statist Assoc. 1970;65:904–912.
- Wei LJ, Lin DY, Weissfeld L. Regression analysis of multivariate incomplete failure time data by modeling marginal distributions. J Am Statist Assoc. 1989;84:1065–1073.
- Lin DY, Sullivan PF. Meta-analysis of genome-wide association studies with overlapping subjects. Am J Hum Genet. 2009;85:862–872.
- Purcell S, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–575.
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