Age-dependent genetic variants associated with longitudinal changes in brain structure across the lifespan

Human brain structure changes throughout our lives. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental, and neurodegenerative diseases. Here, we identified common genetic variants that affect rates of brain growth or atrophy, in the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal MRI data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene-set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and ageing. ### Competing Interest Statement BF has received speaking fees from MEDICE Arzneimittel Putter GmbH & Co. BWJHP has received research funding from Jansen Research and Boehringer Ingelheim. CA has been a consultant to or has received honoraria or grants from Acadia, Angelini, Gedeon Richter, Janssen Cilag, Lundbeck, Minerva, Otsuka, Roche, Sage, Servier, Shire, Schering Plough, Sumitomo Dainippon Pharma, Sunovion and Takeda. CDW is an employee of Biogen Inc. DJS has received research grants and/or consultancy honoraria from Lundbeck and Sun. GJB receives honoraria for teaching from GE Healthcare. HB is on the Advisory Board Nutricia Australia. HEH has received travel fees for membership of the Steering Committee of the Lundbeck Foundation Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research and for two presentations from Philips. These concerned activities unrelated to the submitted work. HJG has received travel grants and speaker's honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care. LP has served as an advisor or consultant to Shire, Takeda and Roche. She has received speaking fees from Shire and Infectopharm. The present work is unrelated to these relationships. MHJ received grant support from the Brain and behavior Foundation (NARSAD) Independent Investigator grant number 20244. MMN has received fees for memberships in Scientific Advisory Boards from the Lundbeck Foundation and the Robert-Bosch-Stiftung, and for membership in the Medical-Scientific Editorial Office of the Deutsches Arzteblatt. MMN was reimbursed travel expenses for a conference participation by Shire Deutschland GmbH. MMN receives salary payments from Life & Brain GmbH and holds shares in Life & Brain GmbH. All these concerned activities outside the submitted work. NJ and PMT are MPI's of a research grant from Biogen, Inc (Boston, USA) for work unrelated to the contents of this manuscript. OAA has received Speaker's honorarium from Lundbeck, Consultant for HealthLytix. PSS reports on-off payment for an advisory board meeting of Biogen. TB served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire, and Infectopharm. He received conference support or speaker's fee by Lilly, Medice, and Shire. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. TEl has received speaker's fee from Lundbeck AS. TRM has received honoraria for speaking and chairing engagements from Lundbeck, Janssen and Astellas. Other authors declare no conflict of interest.