Genetic architecture of brain age and its casual relations with brain and mental disorders

Author:

Leonardsen Esten H.ORCID,Vidal-Piñeiro DidacORCID,Roe James M.ORCID,Frei OleksandrORCID,Shadrin Alexey A.ORCID,Iakunchykova Olena,de Lange Ann-Marie G.ORCID,Kaufmann TobiasORCID,Taschler BerndORCID,Smith Stephen M.,Andreassen Ole A.ORCID,Wolfers ThomasORCID,Westlye Lars T.ORCID,Wang YunpengORCID

Abstract

AbstractThe difference between chronological age and the apparent age of the brain estimated from brain imaging data — the brain age gap (BAG) — is widely considered a general indicator of brain health. Converging evidence supports that BAG is sensitive to an array of genetic and non-genetic traits and diseases, yet few studies have examined the genetic architecture and its corresponding causal relationships with common brain disorders. Here, we estimate BAG using state-of-the-art neural networks trained on brain scans from 53,542 individuals (age range 3-95 years). A genome-wide association analysis across 28,104 individuals (40-84 years) from the UK Biobank revealed eight independent genomic regions significantly associated with BAG (p<5×10−8) implicating neurological, metabolic, and immunological pathways – among which seven are novel. No significant genetic correlations or causal relationships with BAG were found for Parkinson’s disease, major depressive disorder, or schizophrenia, but two-sample Mendelian randomization indicated a causal influence of AD (p=7.9×10−4) and bipolar disorder (p=1.35×10−2) on BAG. These results emphasize the polygenic architecture of brain age and provide insights into the causal relationship between selected neurological and neuropsychiatric disorders and BAG.

Publisher

Cold Spring Harbor Laboratory

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