Genetic influences on the shape of brain ventricular and subcortical structures

Abstract

Brain ventricular and subcortical structures are heritable both in size and shape. Genetic influences on brain region size have been studied using conventional volumetric measures, but little is known about the genetic basis of ventricular and subcortical shapes. Here we developed pipelines to extract seven complementary shape measures for lateral ventricles, subcortical structures, and hippocampal subfields. Based on over 45,000 subjects in the UK Biobank and ABCD studies, 60 genetic loci were identified to be associated with brain shape features, 19 of which were not detectable by volumetric measures of these brain structures. Ventricular and subcortical shape features were genetically related to cognitive functions, mental health traits, and multiple brain disorders, such as the attention-deficit/hyperactivity disorder. Vertex-based shape analysis was performed to precisely localize the brain regions with these shared genetic influences. Mendelian randomization suggests brain shape causally contributes to neurological and neuropsychiatric disorders, including Alzheimer's disease and schizophrenia. Our results uncover the genetic architecture of brain shape for ventricular and subcortical structures and prioritize the genetic factors underlying disease-related shape variations.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This research was partially supported by U.S. NIH grants MH086633 (HT.Z.), MH116527 (TF.L.), and U01HG011720 (Y.L.).

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:

The individual-level data used in the present study have been openly available from the UK Biobank (https://www.ukbiobank.ac.uk/) and ABCD (https://abcdstudy.org/) studies.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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).

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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

Data Availability

The individual-level data used in the present study can be obtained from the UK Biobank (https://www.ukbiobank.ac.uk/) and ABCD (https://abcdstudy.org/) studies. Our GWAS summary statistics will be shared on Zenodo and at the BIG-KP https://bigkp.org/. Our GWAS results will also be available via the interactive web browser at http://165.227.78.169:443/.

https://bigkp.org/

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