Abstract
Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 838 individuals and high-coverage whole-genome sequencing of 449 individuals. We compared polygenic risk scores (PRS), estimated using the latest BP1 genome-wide association study (GWAS) summary statistics, between BP1 individuals and related controls. We also evaluated whether BP1 individuals had a higher burden of rare deleterious single-nucleotide variants (SNVs) and rare copy number variants (CNVs) in a set of genes related to BP1. We found that compared with unaffected relatives, BP1 individuals had higher PRS estimated from BP1 GWAS statistics (P = 0.001 ~ 0.007) and displayed modest increase in burdens of rare deleterious SNVs (P = 0.047) and rare CNVs (P = 0.002 ~ 0.033) in genes related to BP1. We did not observe rare variants segregating in the pedigrees. These results suggest that small-to-moderate effect rare and common variants are more likely to contribute to BP1 risk in these extended pedigrees than a few large-effect rare variants.
Highlights
Bipolar disorder (BP), consisting of episodes of mania and depression, has a heritability from twin studies estimated to be ~80%1
The admixture proportions in the pedigrees overall were associated with bipolar disorder 1 (BP1) status; risk of BP1 increased by Odds ratio (OR) of 1.53 (GLMM p = 0.0008) with every increase
We demonstrate that common variants in extended pedigrees contribute to BP1 risk while observing modest evidence of effect of rare variants on BP1 risk
Summary
Bipolar disorder (BP), consisting of episodes of mania and depression, has a heritability from twin studies estimated to be ~80%1. Disorders, SNP-based genome-wide association studies (GWAS) of large case/control samples have discovered many loci that contribute unequivocally to disease risk but that collectively explain only a small fraction of disease heritability. The most recent published BP GWAS, incorporating >20,000 cases and 30,000 controls, has reported 30 genome-wide significant SNP-associations and SNP-based heritability (h2snp) of 25% for BP12. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
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