Genomic loci influence patterns of structural covariance in the human brain.

Normal and pathologic neurobiological processes influence brain morphology in coordinated ways that give rise to patterns of structural covariance (PSC) across brain regions and individuals during brain aging and diseases. The genetic underpinnings of these patterns remain largely unknown. We apply a stochastic multivariate factorization method to a diverse population of 50,699 individuals (12 studies and 130 sites) and derive data-driven, multi-scale PSCs of regional brain size. PSCs were significantly correlated with 915 genomic loci in the discovery set, 617 of which are newly identified, and 72% were independently replicated. Key pathways influencing PSCs involve reelin signaling, apoptosis, neurogenesis, and appendage development, while pathways of breast cancer indicate potential interplays between brain metastasis and PSCs associated with neurodegeneration and dementia. Using support vector machines, multi-scale PSCs effectively derive imaging signatures of several brain diseases. Our results elucidate genetic and biological underpinnings that influence structural covariance patterns in the human brain.

Déclaration de conflit d'intérêts

Competing interests statement:D.H.W. served as Site PI for studies by Biogen, Merck, and Eli Lilly/Avid. He has received consulting fees from GE Healthcare and Neuronix. He is on the DSMB for a trial sponsored by Functional Neuromodulation. A.J.S. receives support from multiple NIH grants (P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U01 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, U01 AG068057, and U01 AG072177). He has also received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in-kind contribution of PET tracer precursor); Bayer Oncology (Scientific Advisory Board); Eisai (Scientific Advisory Board); Siemens Medical Solutions, Inc. (Dementia Advisory Board); and Springer-Nature Publishing (Editorial Office Support as Editor-in-Chief, Brain Imaging, and Behavior). O.C. reports having received consulting fees from AskBio (2020) and Therapanacea (2022), having received payments for writing a lay audience short paper from Expression Santé (2019), and that his laboratory has received grants (paid to the institution) from Qynapse (2017 to present). Members of his laboratory have co-supervised a Ph.D. thesis with myBrainTechnologies (2016 to 2019) and with Qynapse (2017 to present). O.C.’s spouse is an employee and holds stock options of myBrainTechnologies (2015 to present). O.C. has a patent registered at the International Bureau of the World Intellectual Property Organization (PCT/IB2016/0526993, J.-B. Schiratti, S. Allassonniere, O.C., S. Durrleman, A method for determining the temporal progression of a biological phenomenon and associated methods and devices) (2017). M.E. receives support from multiple NIH grants, the Alzheimer’s Association, and the Alzheimer’s Therapeutic Research Institute. M.V.Z. serves as a consultant and/or speaker for the following pharmaceutical companies: Eurofarma, Lundbeck, Abbott, Greencare, Myralis, and Elleven Healthcare.