학술논문
Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates
Document Type
article
Author
Jae Hoon Sul; Susan K. Service; Alden Y. Huang; Vasily Ramensky; Sun-Goo Hwang; Terri M. Teshiba; YoungJun Park; Anil P. S. Ori; Zhongyang Zhang; Niamh Mullins; Loes M. Olde Loohuis; Scott C. Fears; Carmen Araya; Xinia Araya; Mitzi Spesny; Julio Bejarano; Margarita Ramirez; Gabriel Castrillón; Juliana Gomez-Makhinson; Maria C. Lopez; Gabriel Montoya; Claudia P. Montoya; Ileana Aldana; Javier I. Escobar; Jorge Ospina-Duque; Barbara Kremeyer; Gabriel Bedoya; Andres Ruiz-Linares; Rita M. Cantor; Julio Molina; Giovanni Coppola; Roel A. Ophoff; Gabriel Macaya; Carlos Lopez-Jaramillo; Victor Reus; Carrie E. Bearden; Chiara Sabatti; Nelson B. Freimer
Source
Translational Psychiatry, Vol 10, Iss 1, Pp 1-10 (2020)
Subject
Language
English
ISSN
2158-3188
Abstract
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.