Novel 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, 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 novel, 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 new genetic and biological underpinnings that influence structural covariance patterns in the human brain. Significance statement The coordinated patterns of changes in the human brain throughout life, driven by brain development, aging, and diseases, remain largely unexplored regarding their underlying genetic determinants. This study delineates 2003 multi-scale patterns of structural covariance (PSCs) and identifies 617 novel genomic loci, with the mapped genes enriched in biological pathways implicated in reelin signaling, apoptosis, neurogenesis, and appendage development. Overall, the 2003 PSCs provide new genetic insights into understanding human brain morphological changes and demonstrate great potential in predicting various neurologic conditions. ### Competing Interest Statement Competing interests are detailed in the manuscript. ### Funding Statement The iSTAGING consortium is a multi-institutional effort funded by NIA by RF1 AG054409. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All individual studies were approved by their local corresponding Institutional Review Boards (IRB). The iSTAGING and PHENOM consortia consolidated all individual imaging and clinical data; imputed genotype data were directly downloaded from the UKBB website. Data from the UKBB for this project pertains to application 35148. For iSTAGING, the IRB at the University of Pennsylvania (protocol number: 825722) reviewed the research proposal on August 31st, 2016, and updated it on August 31st, 2022. No human subjects were recruited or scanned. Existing de-identified data will be used in this mega-analysis study pooling data from 17 studies: BLSA, ADNI1, ADNI2, ADNI3, ACCORD-MIND, LookAhead, SPRINT, CARDIA, MESA, SHIP, BIOCARD, WRAP, Penn-ADC, WHIMS-MRI, AIBL, OASIS, UKBB, MESA, HANDLS. For PHENOM, the IRB at the University of Pennsylvania (protocol number: 828077) reviewed the research proposal on August 19th, 2017. No human subjects were recruited or scanned. Existing de-identified data will be used in this meta-analysis study pooling data from 10 studies at Penn, Ludwick-Maximmilian University of Munich, Kings College-London, University of Utrecht, University of Melbourne, University of Cantabria, University of Sao Paolo, Xijing Hospital Shaanxi, Tianjin Anning Hospital, and Institute of Mental Health Peking University. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The GWAS summary statistics corresponding to this study are publicly available on the BRIDGEPORT web portal () and the MEDICINE web portal (). The GWAS summary statistics used in the genetic correlation analyses were fetched from the GWAS Catalog platform (), although each study provided the original links; The GWAS Catalog platform was used to query if the SNPs identified by MuSIC were previously reported.