Phenotypic Association Analyses With Copy Number Variation in Recurrent Depressive Disorder

James Rucker ,Wolfgang Maier,Margarita Rivera,Marcella Rietschel,Katherine E Tansey,Peter Mcguffin,Rudolf Uher,Florian Holsboer,Dalila Pinto,Lisa Jones,Ania Korszun,Martin Preisig,Katherine J Aitchison,Ole Mors,Ian Jones,Michael R Barnes,Stephen W Scherer,Gerome Breen,Ian Craig ,Anne Farmer ,John P Rice ,Michael John Owen ,Nicholas John Craddock ,Sarah Cohen‐Woods

doi:10.1016/j.biopsych.2015.02.025

Abstract

BackgroundDefining the molecular genomic basis of the likelihood of developing depressive disorder is a considerable challenge. We previously associated rare, exonic deletion copy number variants (CNV) with recurrent depressive disorder (RDD). Sex chromosome abnormalities also have been observed to co-occur with RDD. MethodsIn this reanalysis of our RDD dataset (N = 3106 cases; 459 screened control samples and 2699 population control samples), we further investigated the role of larger CNVs and chromosomal abnormalities in RDD and performed association analyses with clinical data derived from this dataset. ResultsWe found an enrichment of Turner’s syndrome among cases of depression compared with the frequency observed in a large population sample (N = 34,910) of live-born infants collected in Denmark (two-sided p = .023, odds ratio = 7.76 [95% confidence interval = 1.79–33.6]), a case of diploid/triploid mosaicism, and several cases of uniparental isodisomy. In contrast to our previous analysis, large deletion CNVs were no more frequent in cases than control samples, although deletion CNVs in cases contained more genes than control samples (two-sided p = .0002). ConclusionsAfter statistical correction for multiple comparisons, our data do not support a substantial role for CNVs in RDD, although (as has been observed in similar samples) occasional cases may harbor large variants with etiological significance. Genetic pleiotropy and sample heterogeneity suggest that very large sample sizes are required to study conclusively the role of genetic variation in mood disorders.

Highlights

Defining the molecular genomic basis of the likelihood of developing depressive disorder is a considerable challenge
We present an analysis of large copy number variants (CNV) and chromosomal aneuploidies in a case-control sample of recurrent depressive disorder (RDD)
After correction for multiple testing, we generally found little evidence for the association of large CNVs with RDD

Summary

Introduction

Defining the molecular genomic basis of the likelihood of developing depressive disorder is a considerable challenge. Exonic deletion copy number variants (CNV) with recurrent depressive disorder (RDD). Sex chromosome abnormalities have been observed to co-occur with RDD. METHODS: In this reanalysis of our RDD dataset (N 5 3106 cases; 459 screened control samples and 2699 population control samples), we further investigated the role of larger CNVs and chromosomal abnormalities in RDD and performed association analyses with clinical data derived from this dataset. CONCLUSIONS: After statistical correction for multiple comparisons, our data do not support a substantial role for CNVs in RDD, (as has been observed in similar samples) occasional cases may harbor large variants with etiological significance. Genetic pleiotropy and sample heterogeneity suggest that very large sample sizes are required to study conclusively the role of genetic variation in mood disorders

Methods

Results

Conclusion