Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder
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2017-01-10Author
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<jats:title>Abstract</jats:title><jats:p>We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; <jats:italic>P</jats:italic>=3.28 × 10<jats:sup>−8</jats:sup>) that includes the brain-enriched cytoskeleton protein adducin 3 (<jats:italic>ADD3),</jats:italic> a non-coding RNA, and a neuropeptide-specific aminopeptidase P (<jats:italic>XPNPEP1)</jats:italic>. Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP-<jats:italic>h</jats:italic><jats:sup>2</jats:sup>=0.35; BD II SNP-<jats:italic>h</jats:italic><jats:sup>2</jats:sup>=0.25; <jats:italic>P</jats:italic>=0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.</jats:p>
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