Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder

Alexander Charney ,Humberto Nicolini ,Sarah E Bergen ,Arianna Di Florio ,Douglas S Lehrer ,Douglas M Ruderfer ,Evelyn J Bromet ,Steven A Mccarroll ,Dolores Malaspina ,Jeffrey J Rakofsky ,Christina M Hultman ,Ian Jones ,Eli A Stahl ,Roy H Perlis ,P H Lee ,Shaun Purcell ,Jennifer L Moran ,Panos Roussos ,Michele T Pato ,Nicholas John Craddock ,James A Knowles ,Rich Belliveau ,Carlos N Pato ,Christopher P Morley ,Laura J Fochtmann ,Stephen R Marder ,Liz Forty ,Anders Juréus ,Mark Hyman Rapaport ,Katherine Gordon‐Smith ,Paul Lichtenstein ,Lisa Jones ,Kimberly Chambert ,Peter F Buckley ,E K Green ,Janet L Sobell ,Mikael Landén ,Ayman H Fanous ,Lena Backlund ,Jordan W Smoller ,Diana O Perkins ,Michael Escamilla ,Helena Medeiros ,Martin Schalling ,Pamela Sklar

doi:10.1038/tp.2016.242

Abstract

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; P=3.28 × 10−8) that includes the brain-enriched cytoskeleton protein adducin 3 (ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P (XPNPEP1). 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-h2=0.35; BD II SNP-h2=0.25; P=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.

Highlights

Bipolar disorder (BD) is a mental illness characterized by episodes of mania and depression
Genome-wide single nucleotide polymorphisms (SNPs) data of 6447 BD cases and 12 639 controls matched for ancestry were analyzed from a previously unreported population-based sampling in Sweden, the United Kingdom and the United States (Supplementary Figure 1)
Neither variant has been previously reported to have an association with BD, major depressive disorder (MDD), or SCZ

Summary

Introduction

Bipolar disorder (BD) is a mental illness characterized by episodes of mania and depression. We compare SNP-based measures of heritability population-based study of 435 000 patients with SCZ, 40 000 and genetic correlation for BD I and BD II, and assess the polygenic patients with BD and their family members found an increased risk of BD in first-degree relatives of SCZ probands, and vice versa.[16,17] loading of BD subtypes for risk alleles identified previously through large-scale GWAS of three psychiatric disorders (BD, Compared with SCZ and BD, there is evidence that SA shows SCZ and MDD).

Results

Conclusion