Genome-wide meta-analysis of insomnia prioritizes genes associated with metabolic and psychiatric pathways

TY - JOUR

T1 - Genome-wide meta-analysis of insomnia prioritizes genes associated with metabolic and psychiatric pathways

AU - Watanabe, Kyoko

AU - Jansen, Philip R

AU - Savage, Jeanne E

AU - Nandakumar, Priyanka

AU - Wang, Xin

AU - Hinds, David A

AU - Gelernter, Joel

AU - Levey, Daniel F

AU - Polimanti, Renato

AU - Stein, Murray B

AU - Van Someren, Eus J W

AU - Smit, August B

AU - Posthuma, Danielle

N1 - © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2022/7/14

Y1 - 2022/7/14

N2 - Insomnia is a heritable, highly prevalent sleep disorder for which no sufficient treatment currently exists. Previous genome-wide association studies with up to 1.3 million subjects identified over 200 associated loci. This extreme polygenicity suggested that many more loci remain to be discovered. The current study almost doubled the sample size to 593,724 cases and 1,771,286 controls, thereby increasing statistical power, and identified 554 risk loci (including 364 novel loci). To capitalize on this large number of loci, we propose a novel strategy to prioritize genes using external biological resources and functional interactions between genes across risk loci. Of all 3,898 genes naively implicated from the risk loci, we prioritize 289 and find brain-tissue expression specificity and enrichment in specific gene sets of synaptic signaling functions and neuronal differentiation. We show that this novel gene prioritization strategy yields specific hypotheses on underlying mechanisms of insomnia that would have been missed by traditional approaches.

AB - Insomnia is a heritable, highly prevalent sleep disorder for which no sufficient treatment currently exists. Previous genome-wide association studies with up to 1.3 million subjects identified over 200 associated loci. This extreme polygenicity suggested that many more loci remain to be discovered. The current study almost doubled the sample size to 593,724 cases and 1,771,286 controls, thereby increasing statistical power, and identified 554 risk loci (including 364 novel loci). To capitalize on this large number of loci, we propose a novel strategy to prioritize genes using external biological resources and functional interactions between genes across risk loci. Of all 3,898 genes naively implicated from the risk loci, we prioritize 289 and find brain-tissue expression specificity and enrichment in specific gene sets of synaptic signaling functions and neuronal differentiation. We show that this novel gene prioritization strategy yields specific hypotheses on underlying mechanisms of insomnia that would have been missed by traditional approaches.

U2 - 10.1038/s41588-022-01124-w

DO - 10.1038/s41588-022-01124-w

M3 - Article

C2 - 35835914

SN - 1061-4036

VL - 54

SP - 1125

EP - 1132

JO - Nature Genetics

JF - Nature Genetics

ER -