title: Genome-wide association analysis of age at onset and psychotic symptoms in bipolar disorder.
abstract: Genome-wide association studies (GWAS) have identified several susceptibility loci for bipolar disorder (BP), most notably ANK3. However, most of the inherited risk for BP remains unexplained. One reason for the limited success may be the genetic heterogeneity of BP. Clinical sub-phenotypes of BP may identify more etiologically homogeneous subsets of patients, which can be studied with increased power to detect genetic variation. Here, we report on a mega-analysis of two widely studied sub-phenotypes of BP, age at onset and psychotic symptoms, which are familial and clinically significant. We combined data from three GWAS: NIMH Bipolar Disorder Genetic Association Information Network (GAIN-BP), NIMH Bipolar Disorder Genome Study (BiGS), and a German sample. The combined sample consisted of 2,836 BP cases with information on sub-phenotypes and 2,744 controls. Imputation was performed, resulting in 2.3 million SNPs available for analysis. No SNP reached genome-wide significance for either sub-phenotype. In addition, no SNP reached genome-wide significance in a meta-analysis with an independent replication sample. We had 80% power to detect associations with a common SNP at an OR of 1.6 for psychotic symptoms and a mean difference of 1.8 years in age at onset. Age at onset and psychotic symptoms in BP may be influenced by many genes of smaller effect sizes or other variants not measured well by SNP arrays, such as rare alleles.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Belmonte Mahon
authors.forename: Mehdi
authors.initials: M
authors.lastname: Pirooznia
authors.forename: Fernando S
authors.initials: FS
authors.lastname: Goes
authors.forename: Fayaz
authors.initials: F
authors.lastname: Seifuddin
authors.forename: Jo
authors.initials: J
authors.lastname: Steele
authors.forename: Phil Hyoun
authors.initials: PH
authors.lastname: Lee
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.forename: Marian L
authors.initials: ML
authors.lastname: Hamshere
authors.forename: J Raymond
authors.initials: JR
authors.lastname: Depaulo
authors.forename: John R
authors.initials: JR
authors.lastname: Kelsoe
authors.forename: Marcella
authors.initials: M
authors.lastname: Rietschel
authors.forename: Markus
authors.initials: M
authors.lastname: Nöthen
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Hugh
authors.initials: H
authors.lastname: Gurling
authors.forename: Shaun
authors.initials: S
authors.lastname: Purcell
authors.forename: Jordan W
authors.initials: JW
authors.lastname: Smoller
authors.forename: Nick
authors.initials: N
authors.lastname: Craddock
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Schulze
authors.forename: Francis J
authors.initials: FJ
authors.lastname: McMahon
authors.forename: James B
authors.initials: JB
authors.lastname: Potash
authors.forename: Peter P
authors.initials: PP
authors.lastname: Zandi
mesh_terms: D017668:Age of Onset; D001714:Bipolar Disorder / Q000150:complications / Q000453:epidemiology* / Q000235:genetics*; D003710:Demography; D005260:Female; D055106:Genome-Wide Association Study; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008297:Male; D011618:Psychotic Disorders / Q000150:complications / Q000453:epidemiology* / Q000235:genetics*; D055815:Young Adult