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

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.

• Autores: Bedoya Berrío, Gabriel de Jesús; Gómez Makhinson, Juliana; López Tobón, María Cecilia; Montoya Montoya, Gabriel Jaime; Montoya Guerra, Claudia Patricia; Ospina Duque, Jorge; López Jaramillo, Carlos Alberto; Ruíz Linares, Andrés; Ori, Anil P S; Zhang, Zhongyang; Mullins, Niamh; Olde Loohuis, Loes M; Fears, Scott C; Araya, Carmen; Araya, Xinia; Spesny, Mitzi; Bejarano, Julio; Ramírez, Margarita; Castrillón, Gabriel; Hoon Sul, Jae; Service, Susan K.; Huang, Alden Y.; Ramensky, Vasily; Aldana, Ileana; Escobar, Javier I.; Hwang, Sun-Goo; Kremeyer, Barbara; Park, YoungJun; Cantor, Rita M.; Molina, Julio; Coppola, Giovanni; Ophoff, Roel A.; Macaya, Gabriel; Teshiba, Terri M.; Reus, Víctor; Bearden, Carrie E.; Sabatti, Chiara; Freimer, Nelson B.
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2020
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/41112
• Acceso en línea: https://hdl.handle.net/10495/41112
• Palabra clave: Bipolar Disorder; Trastorno Bipolar; Genetic Predisposition to Disease; Predisposición Genética a la Enfermedad; Genome-Wide Association Study; Estudio de Asociación del Genoma Completo; Polymorphism, Single Nucleotide; Polimorfismo de Nucleótido Simple; Pedigree; Linaje; https://id.nlm.nih.gov/mesh/D001714; https://id.nlm.nih.gov/mesh/D020022; https://id.nlm.nih.gov/mesh/D055106; https://id.nlm.nih.gov/mesh/D020641; https://id.nlm.nih.gov/mesh/D010375
• Rights: openAccess
• License: https://creativecommons.org/licenses/by/4.0/