Rare variant association study of veteran twin whole-genomes links severe depression with a nonsynonymous change in the neuronal gene BHLHE22

Abstract

Objectives

Major Depressive Disorder (MDD) is a complex neuropsychiatric disease with known genetic associations, but without known links to rare variation in the human genome. Here we aim to identify rare genetic variants associated with MDD using deep whole-genome sequencing data in an independent population.

Methods

We report the sequencing of 1,688 whole genomes in a large sample of male-male Veteran twins. Depression status was classified based on a structured diagnostic interview according to DSM-III-R diagnostic criteria. Searching only rare variants in genomic regions from recent GWAS on MDD, we used the optimised sequence kernel association test and Fisher's Exact test to fine map loci associated with severe depression.

Results

Our analysis identified one gene associated with severe depression, basic helix loop helix e22 (P_Adjusted = 0.03) via SKAT-O test between unrelated severely depressed cases compared to unrelated non-depressed controls. The same gene BHLHE22 had a non-silent variant rs13279074 (P_Adjusted = 0.032) based on a single variant Fisher’s Exact test between unrelated severely depressed cases compared to unrelated non-depressed controls.

Conclusion

The gene BHLHE22 shows compelling genetic evidence of directly impacting the severe depression phenotype. Together these results advance understanding of the genetic contribution to major depressive disorder in a new cohort and link a rare variant to severe forms of the disorder.

Keywords:

• MDD
• GWAS
• rare variant
• BHLHe22
• depression
• whole-genome sequencing

Acknowlegements

We want to acknowledge the participants and investigators of FinnGen study. Most importantly, the authors gratefully acknowledge the cooperation and participation of the members of the VET Registry and their families. Without their contribution this research would not have been possible.

Disclosure statement

All statements and opinions are solely of the authors and do not necessarily reflect the position or policy of the VET Registry, the VA, or the United States Government. The opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the U.S. Army, Department of Defense, the U.S. Government or the Uniformed Services University of the Health Sciences. The use of trade names does not constitute an official endorsement or approval of the use of such reagents or commercial hardware or software. This document may not be cited for purposes of advertisement. The authors report no conflict of interest.

Data availability statement

Investigators interested in accessing phenotypic and genotypic data from the VET Registry (https://www.seattle.eric.research.va.gov/VETR/Home.asp) can apply for data access by contacting the VET Registry at [email protected].

Additional information

Funding

This work was supported by NHLBI/NIH under grant IAA-AA-HL-14-007 (Pollard); Cooperative Studies Program (CSP) of the United States Department of Veterans Affairs (VA) Office of Research & Development; R01DA004604 (Tsuang); R01AG050595 (Kremen, Lyons, Franz) and R01AG022381 (Kremen); and R01HL68630, R01AG026255, R01HL125246, and R01HL136205 (Vaccarino).