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Understanding the genetic determinants of the brain with MOSTest.

ABSTRACT: Regional brain morphology has a complex genetic architecture, consisting of many common polymorphisms with small individual effects. This has proven challenging for genome-wide association studies (GWAS). Due to the distributed nature of genetic signal across brain regions, multivariate analysis of regional measures may enhance discovery of genetic variants. Current multivariate approaches to GWAS are ill-suited for complex, large-scale data of this kind. Here, we introduce the Multivariate Omnibus Statistical Test (MOSTest), with an efficient computational design enabling rapid and reliable inference, and apply it to 171 regional brain morphology measures from 26,502 UK Biobank participants. At the conventional genome-wide significance threshold of ??=?5?×?10^-8, MOSTest identifies 347 genomic loci associated with regional brain morphology, more than any previous study, improving upon the discovery of established GWAS approaches more than threefold. Our findings implicate more than 5% of all protein-coding genes and provide evidence for gene sets involved in neuron development and differentiation.

SUBMITTER: van der Meer D

PROVIDER: S-EPMC7360598 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Understanding the genetic determinants of the brain with MOSTest.

van der Meer Dennis D Frei Oleksandr O Kaufmann Tobias T Shadrin Alexey A AA Devor Anna A Smeland Olav B OB Thompson Wesley K WK Fan Chun Chieh CC Holland Dominic D Westlye Lars T LT Andreassen Ole A OA Dale Anders M AM

Nature communications 20200714 1

Regional brain morphology has a complex genetic architecture, consisting of many common polymorphisms with small individual effects. This has proven challenging for genome-wide association studies (GWAS). Due to the distributed nature of genetic signal across brain regions, multivariate analysis of regional measures may enhance discovery of genetic variants. Current multivariate approaches to GWAS are ill-suited for complex, large-scale data of this kind. Here, we introduce the Multivariate Omni ...[more]

PMID: 32665545

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Project description:ObjectiveTo test the hypothesis of 'horizontal epidemiology', i.e. that psychosocial difficulties (PSDs), such as sleep disturbances, emotional instability and difficulties in personal interactions, and their environmental determinants are experienced in common across neurological and psychiatric disorders, together called brain disorders.Study designA multi-method study involving systematic literature reviews, content analysis of patient-reported outcomes and outcome instruments, clinical input and a qualitative study was carried out to generate a pool of PSD and environmental determinants relevant for nine different brain disorders, namely epilepsy, migraine, multiple sclerosis, Parkinson's disease, stroke, dementia, depression, schizophrenia and substance dependency. Information from these sources was harmonized and compiled, and after feedback from external experts, a data collection protocol including PSD and determinants common across these nine disorders was developed. This protocol was implemented as an interview in a cross-sectional study including a convenience sample of persons with one of the nine brain disorders. PSDs endorsed by at least 25% of patients with a brain disorder were considered associated with the disorder. PSD were considered common across disorders if associated to 5 out of the 9 brain disorders and if among the 5 both neurological and psychiatric conditions were represented.SettingThe data collection protocol with 64 PSDs and 20 determinants was used to collect data from a convenience sample of 722 persons in four specialized health care facilities in Europe.Results57 of the PSDs and 16 of the determinants included in the protocol were found to be experienced across brain disorders.ConclusionThis is the first evidence that supports the hypothesis of horizontal epidemiology in brain disorders. This result challenges the brain disorder-specific or vertical approach in which clinical and epidemiological research about psychosocial difficulties experienced in daily life is commonly carried in neurology and psychiatry and the way in which the corresponding health care delivery is practiced in many countries of the world.

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Understanding the genetic determinants of the brain with MOSTest.

Publications

Understanding the genetic determinants of the brain with MOSTest.

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