Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates

作者：Jae Hoon Sul, Susan K. Service, Alden Huang, Vasily E. Ramensky, Sun‐Goo Hwang, Terri M. Teshiba, Young‐Jun 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, María Cecilia López, Gabriel Montoya, Claudia Patricia Montoya, Ileana Aldana, Javier I. Escobar, Jorge Ospina‐Duque, Bárbara Kremeyer, Gabriel Bedoya, Andrés Ruiz‐Linares, Rita M. Cantor, Julio Molina, Giovanni Coppola, Roel A. Ophoff, Gabriel Macaya, Carlos López‐Jaramillo, Victor I. Reus, Carrie E. Bearden, Chiara Sabatti, Nelson B. Freimer · 发表于：Translational Psychiatry · 年份：2020 · DOI：10.1038/s41398-020-0758-1 · 被引用次数：39 · 研究领域：Genetic Associations and Epidemiology、Genomic variations and chromosomal abnormalities、Genomics and Rare Diseases

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 ...