Dataset Information

Genetic architecture of brain age and its causal relations with brain and mental disorders.

ABSTRACT: The 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 nongenetic 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.

SUBMITTER: Leonardsen EH

PROVIDER: S-EPMC10615751 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Genetic architecture of brain age and its causal relations with brain and mental disorders.

Leonardsen Esten H EH Vidal-Piñeiro Didac D Roe James M JM Frei Oleksandr O Shadrin Alexey A AA Iakunchykova Olena O de Lange Ann-Marie G AG Kaufmann Tobias T Taschler Bernd B Smith Stephen M SM Andreassen Ole A OA Wolfers Thomas T Westlye Lars T LT Wang Yunpeng Y

Molecular psychiatry 20230510 7

The 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 nongenetic 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 ...[more]

PMID: 37165155

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Project description:Both psychiatric vulnerability and cortical structure are shaped by the cumulative effect of common genetic variants across the genome. However, the shared genetic underpinnings between psychiatric disorders and brain structural phenotypes, such as thickness and surface area of the cerebral cortex, remains elusive. In this study, we employed pleiotropy-informed conjunctional false discovery rate analysis to investigate shared loci across genome-wide association scans of regional cortical thickness, surface area, and seven psychiatric disorders in approximately 700,000 individuals of European ancestry. Aggregating regional measures, we identified 50 genetic loci shared between psychiatric disorders and surface area, as well as 26 genetic loci shared with cortical thickness. Risk alleles exhibited bidirectional effects on both cortical thickness and surface area, such that some risk alleles for each disorder increased regional brain size while other risk alleles decreased regional brain size. Due to bidirectional effects, in many cases we observed extensive pleiotropy between an imaging phenotype and a psychiatric disorder even in the absence of a significant genetic correlation between them. The impact of genetic risk for psychiatric disorders on regional brain structure did exhibit a consistent pattern across highly comorbid psychiatric disorders, with 80% of the genetic loci shared across multiple disorders displaying consistent directions of effect. Cortical patterning of genetic overlap revealed a hierarchical genetic architecture, with the association cortex and sensorimotor cortex representing two extremes of shared genetic influence on psychiatric disorders and brain structural variation. Integrating multi-scale functional annotations and transcriptomic profiles, we observed that shared genetic loci were enriched in active genomic regions, converged on neurobiological and metabolic pathways, and showed differential expression in postmortem brain tissue from individuals with psychiatric disorders. Cumulatively, these findings provide a significant advance in our understanding of the overlapping polygenic architecture between psychopathology and cortical brain structure.

Dataset Information

Genetic architecture of brain age and its causal relations with brain and mental disorders.

Publications

Genetic architecture of brain age and its causal relations with brain and mental disorders.

Similar Datasets

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