Genome-wide association analysis of age at onset and psychotic symptoms in bipolar disorder

Pamela Belmonte Mahon, Mehdi Pirooznia, Fernando S. Goes, Fayaz Seifuddin, Jo Steele, Phil Hyoun Lee, Jie Huang, Marian L. Hamshere, J. Raymond DePaulo, John R. Kelsoe, Marcella Rietschel, Markus Nöthen, Sven Cichon, Hugh Gurling, Shaun Purcell, Jordan W. Smoller, Nick Craddock, Thomas G. Schulze, Francis J. Mcmahon, James B. PotashPeter P. Zandi

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


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.

Original languageEnglish
Pages (from-to)370-378
Number of pages9
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Issue number3
StatePublished - Apr 2011
Externally publishedYes


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