title: Genomic view of bipolar disorder revealed by whole genome sequencing in a genetic isolate.
abstract: Bipolar disorder is a common, heritable mental illness characterized by recurrent episodes of mania and depression. Despite considerable effort to elucidate the genetic underpinnings of bipolar disorder, causative genetic risk factors remain elusive. We conducted a comprehensive genomic analysis of bipolar disorder in a large Old Order Amish pedigree. Microsatellite genotypes and high-density SNP-array genotypes of 388 family members were combined with whole genome sequence data for 50 of these subjects, comprising 18 parent-child trios. This study design permitted evaluation of candidate variants within the context of haplotype structure by resolving the phase in sequenced parent-child trios and by imputation of variants into multiple unsequenced siblings. Non-parametric and parametric linkage analysis of the entire pedigree as well as on smaller clusters of families identified several nominally significant linkage peaks, each of which included dozens of predicted deleterious variants. Close inspection of exonic and regulatory variants in genes under the linkage peaks using family-based association tests revealed additional credible candidate genes for functional studies and further replication in population-based cohorts. However, despite the in-depth genomic characterization of this unique, large and multigenerational pedigree from a genetic isolate, there was no convergence of evidence implicating a particular set of risk loci or common pathways. The striking haplotype and locus heterogeneity we observed has profound implications for the design of studies of bipolar and other related disorders.
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Georgi
authors.affiliation: The Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Craig
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Kember
authors.affiliation: Department of Neuroscience, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Wencheng
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Lindquist
authors.affiliation: The Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Sara
authors.initials: S
authors.lastname: Nasser
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Brown
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Janice A
authors.initials: JA
authors.lastname: Egeland
authors.affiliation: Department of Neuroscience, University of Miami Miller School of Medicine, Miami, Florida, United States of America; Department of Pharmacology, Weill Cornell Medical College, New York, New York, United States of America; Department of Psychiatry, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Paul
authors.affiliation: Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Maja
authors.initials: M
authors.lastname: Bućan
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics* / Q000473:pathology; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D005838:Genotype; D006239:Haplotypes; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D018895:Microsatellite Repeats; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide