Older molecular brain age in severe mental illness. Mol Psychiatry 2021 Jul;26(7):3646-3656
Date
07/08/2020Pubmed ID
32632206Pubmed Central ID
PMC7785531DOI
10.1038/s41380-020-0834-1Scopus ID
2-s2.0-85087558680 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
Psychiatric disorders are associated with accelerated aging and enhanced risk for neurodegenerative disorders. Brain aging is associated with molecular, cellular, and structural changes that are robust on the group level, yet show substantial inter-individual variability. Here we assessed deviations in gene expression from normal age-dependent trajectories, and tested their validity as predictors of risk for major mental illnesses and neurodegenerative disorders. We performed large-scale gene expression and genotype analyses in postmortem samples of two frontal cortical brain regions from 214 control subjects aged 20-90 years. Individual estimates of "molecular age" were derived from age-dependent genes, identified by robust regression analysis. Deviation from chronological age was defined as "delta age". Genetic variants associated with deviations from normal gene expression patterns were identified by expression quantitative trait loci (cis-eQTL) of age-dependent genes or genome-wide association study (GWAS) on delta age, combined into distinct polygenic risk scores (PRScis-eQTL and PRSGWAS), and tested for predicting brain disorders or pathology in independent postmortem expression datasets and clinical cohorts. In these validation datasets, molecular ages, defined by 68 and 76 age-related genes for two brain regions respectively, were positively correlated with chronological ages (r = 0.88/0.91), elevated in bipolar disorder (BP) and schizophrenia (SCZ), and unchanged in major depressive disorder (MDD). Exploratory analyses in independent clinical datasets show that PRSs were associated with SCZ and MDD diagnostics, and with cognition in SCZ and pathology in Alzheimer's disease (AD). These results suggest that older molecular brain aging is a common feature of severe mental illnesses and neurodegeneration.
Author List
Lin CW, Chang LC, Ma T, Oh H, French B, Puralewski R, Mathews F, Fang Y, Lewis DA, Kennedy JL, Mueller D, Marshe VS, Jaffe A, Chen Q, Ursini G, Weinberger D, Newman AB, Lenze EJ, Nikolova YS, Tseng GC, Sibille EAuthor
Chien-Wei Lin PhD Associate Professor in the Data Science Institute department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
BrainDepressive Disorder, Major
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Mental Disorders
