Genetic architecture of epigenetic cortical clock age in brain tissue from older individuals: alterations in CD46 and other loci
Francine Grodstein,
Bernardo Lemos,
Jingyun Yang,
Katia de Paiva Lopes,
Ricardo A. Vialle,
Nicholas Seyfried,
Yanling Wang,
Gemma Shireby,
Eilis Hannon,
Alan Thomas,
Keeley Brookes,
Jonathan Mill,
Philip L. De Jager,
David A. Bennett
Affiliations
Francine Grodstein
Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
Bernardo Lemos
Coit Center for Longevity and Neurotherapeutics, Department of Pharmacology and Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, AZ, USA
Jingyun Yang
Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
Katia de Paiva Lopes
Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
Ricardo A. Vialle
Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
Nicholas Seyfried
Department of Biochemistry, and Center for Neurodegenerative Diseases, Emory University, Atlanta, GA, USA
Yanling Wang
Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
Gemma Shireby
Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK
Eilis Hannon
Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK
Alan Thomas
Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK
Keeley Brookes
Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, UK
Jonathan Mill
Department of Clinical and Biomedical Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK
Philip L. De Jager
Center for Translational and Computational Neuroimmunology, Department of Neurology, and Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
David A. Bennett
Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
The cortical epigenetic clock was developed in brain tissue as a biomarker of brain aging. As one way to identify mechanisms underlying aging, we conducted a GWAS of cortical age. We leveraged postmortem cortex tissue and genotyping array data from 694 participants of the Rush Memory and Aging Project and Religious Orders Study (ROSMAP; 11000,000 SNPs), and meta-analysed ROSMAP with 522 participants of Brains for Dementia Research (5,000,000 overlapping SNPs). We confirmed results using eQTL (cortical bulk and single nucleus gene expression), cortical protein levels (ROSMAP), and phenome-wide association studies (clinical/neuropathologic phenotypes, ROSMAP). In the meta-analysis, the strongest association was rs4244620 (p = 1.29 × 10−7), which also exhibited FDR-significant cis-eQTL effects for CD46 in bulk and single nucleus (microglia, astrocyte, oligodendrocyte, neuron) cortical gene expression. Additionally, rs4244620 was nominally associated with lower cognition, faster slopes of cognitive decline, and greater Parkinsonian signs (n ~ 1700 ROSMAP with SNP/phenotypic data; all p ≤ 0.04). In ROSMAP alone, the top SNP was rs4721030 (p = 8.64 × 10−8) annotated to TMEM106B and THSD7A. Further, in ROSMAP (n = 849), TMEM106B and THSD7A protein levels in cortex were related to many phenotypes, including greater AD pathology and lower cognition (all p ≤ 0.0007). Overall, we identified converging evidence of CD46 and possibly TMEM106B/THSD7A for potential roles in cortical epigenetic clock age.
