Genome-Wide Significant Risk Loci for Mood Disorders in the Old Order Amish Founder Population

Authors

Elizabeth M Humphries
Kwangmi Ahn
Rachel L Kember
Fabiana L Lopes
Evelina Mocci
Juan M Peralta
John Blangero
David C Glahn
Fernando S Goes
Peter P Zandi
Peter Kochunov
Cristopher Van Hout
Alan R Shuldiner
Toni I Pollin
Braxton D Mitchell
Maja Bucan
L Elliot Hong
Francis J McMahon
Seth A Ament

Publication Date

12-1-2023

Journal

Molecular Psychiatry

Abstract

Genome-wide association studies (GWAS) of mood disorders in large case-control cohorts have identified numerous risk loci, yet pathophysiological mechanisms remain elusive, primarily due to the very small effects of common variants. We sought to discover risk variants with larger effects by conducting a genome-wide association study of mood disorders in a founder population, the Old Order Amish (OOA, n = 1,672). Our analysis revealed four genome-wide significant risk loci, all of which were associated with >2-fold relative risk. Quantitative behavioral and neurocognitive assessments (n = 314) revealed effects of risk variants on sub-clinical depressive symptoms and information processing speed. Network analysis suggested that OOA-specific risk loci harbor novel risk-associated genes that interact with known neuropsychiatry-associated genes via gene interaction networks. Annotation of the variants at these risk loci revealed population-enriched, non-synonymous variants in two genes encoding neurodevelopmental transcription factors, CUX1 and CNOT1. Our findings provide insight into the genetic architecture of mood disorders and a substrate for mechanistic and clinical studies.

Keywords

Humans, Genome-Wide Association Study, Male, Female, Genetic Predisposition to Disease, Mood Disorders, Middle Aged, Polymorphism, Single Nucleotide, Amish, Adult, Case-Control Studies, Transcription Factors, Risk Factors, Genetic Loci, Repressor Proteins, Aged, Homeodomain Proteins, Founder Effect, Nuclear Proteins

Comments

Supplementary Materials

PMID: 36882501