Genetic architecture of epigenetic and neuronal ageing rates in human brain regions

• Published in: Nature communications Vol. 8; no. 1; p. 15353
• Main Authors: Lu, Ake T., Hannon, Eilis, Levine, Morgan E., Crimmins, Eileen M., Lunnon, Katie, Mill, Jonathan, Geschwind, Daniel H., Horvath, Steve
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.05.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 45/43; 45/91; 631/208/176/1988; 631/208/205/2138; Adolescent; Adult; Age; Aged; Aged, 80 and over; Aging; Aging - genetics; Alzheimer's disease; Biomarkers; Brain; Brain - metabolism; Brain - pathology; Brain Mapping; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Child; Child, Preschool; Cognitive Dysfunction - genetics; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - pathology; DNA Methylation; Epigenesis, Genetic; Epigenetics; Female; Gene loci; Genome, Human; Genome-Wide Association Study; Genomes; Gerontology; Humanities and Social Sciences; Humans; Infant; Male; Middle Aged; multidisciplinary; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Neurodegenerative Diseases - pathology; Neurons - metabolism; Neurons - pathology; Parkinson's disease; Quantitative Trait Loci; Schizophrenia; Science; Science (multidisciplinary); Los Angeles California; California; United Kingdom > UK; United States > US
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15353

Identifying genes regulating the pace of epigenetic ageing represents a new frontier in genome-wide association studies (GWASs). Here using 1,796 brain samples from 1,163 individuals, we carry out a GWAS of two DNA methylation-based biomarkers of brain age: the epigenetic ageing rate and estimated proportion of neurons. Locus 17q11.2 is significantly associated ( P =4.5 × 10 −9 ) with the ageing rate across five brain regions and harbours a cis -expression quantitative trait locus for EFCAB5 ( P =3.4 × 10 −20 ). Locus 1p36.12 is significantly associated ( P =2.2 × 10 −8 ) with epigenetic ageing of the prefrontal cortex, independent of the proportion of neurons. Our GWAS of the proportion of neurons identified two genome-wide significant loci (10q26 and 12p13.31) and resulted in a gene set that overlaps significantly with sets found by GWAS of age-related macular degeneration ( P =1.4 × 10 −12 ), ulcerative colitis ( P <1.0 × 10 −20 ), type 2 diabetes ( P =2.8 × 10 −13 ), hip/waist circumference in men ( P =1.1 × 10 −9 ), schizophrenia ( P =1.6 × 10 −9 ), cognitive decline ( P =5.3 × 10 −4 ) and Parkinson’s disease ( P =8.6 × 10 −3 ). Studies on the ‘epigenetic clock’, a recently identified ageing biomarker, suggest that pathology might be linked to tissue-specific accelerated ageing. Here, the authors investigate ageing in the human brain and identify genetic loci associated with accelerated ageing in different brain regions.