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

Sul, Jae Hoon; Service, Susan K; Huang, Alden Y; Ramensky, Vasily; Hwang, Sun-Goo; Teshiba, Terri M; Park, YoungJun; Ori, Anil P S; Zhang, Zhongyang; Mullins, Niamh; Olde Loohuis, Loes M; Fears, Scott C; Araya, Carmen; Araya, Xinia; Spesny, Mitzi; Bejarano, Julio; Ramirez, Margarita; Castrillón, Gabriel; Gomez-Makhinson, Juliana; Lopez, Maria C; Montoya, Gabriel; Montoya, Claudia P; Aldana, Ileana; Escobar, Javier I; Ospina-Duque, Jorge; Kremeyer, Barbara; Bedoya, Gabriel; Ruiz-Linares, Andres; Cantor, Rita M; Molina, Julio; Coppola, Giovanni; Ophoff, Roel A; Macaya, Gabriel; Lopez-Jaramillo, Carlos; Reus, Victor; Bearden, Carrie E; Sabatti, Chiara; Freimer, Nelson B     «

Sul, Jae Hoon; Service, Susan K; Huang, Alden Y; Ramensky, Vasily; Hwang, Sun-Goo; Teshiba, Terri M; Park, YoungJun; Ori, Anil P S; Zhang, Zhongyang; Mullins, Niamh; Olde Loohuis, Loes M; Fears, Scott C; Araya, Carmen; Araya, Xinia; Spesny, Mitzi; Bejarano, Julio; Ramirez, Margarita; Castrillón, Gabriel; Gomez-Makhinson, Juliana; Lopez, Maria C; Montoya, Gabriel; Montoya, Claudia P; Aldana, Ileana; Escobar, Javier I; Ospina-Duque, Jorge; Kremeyer, Barbara; Bedoya, Gabriel; Ruiz-Linares, Andres;...     »

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.      «

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...     »