A method to decipher pleiotropy by detecting underlying heterogeneity driven by hidden subgroups applied to autoimmune and neuropsychiatric diseases.

Nat Genet
Authors
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).

Year of Publication
2016
Journal
Nat Genet
Volume
48
Issue
7
Pages
803-10
Date Published
2016 Jul
ISSN
1546-1718
URL
DOI
10.1038/ng.3572
PubMed ID
27182969
PubMed Central ID
PMC4925284
Links
Grant list
U19 AI111224 / AI / NIAID NIH HHS / United States
T32 HG002295 / HG / NHGRI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
U01 GM092691 / GM / NIGMS NIH HHS / United States
U01 DK062418 / DK / NIDDK NIH HHS / United States
R01 AR063759 / AR / NIAMS NIH HHS / United States
UH2 AR067677 / AR / NIAMS NIH HHS / United States