Emerging Methods and Resources for Biological Interrogation of Neuropsychiatric Polygenic Signal

Emil Uffelmann, Danielle Posthuma*

*Corresponding author for this work

Research output: Contribution to JournalReview articleAcademicpeer-review

Abstract

Most neuropsychiatric disorders are highly polygenic, implicating hundreds to thousands of causal genetic variants that span much of the genome. This widespread polygenicity complicates biological understanding because no single variant can explain disease etiology. A strategy to advance biological insight is to seek convergent functions among the large set of variants and map them to a smaller set of disease-relevant genes and pathways. Accordingly, functional genomic resources that provide data on intermediate molecular phenotypes, such as gene-expression and methylation status, can be leveraged to functionally annotate variants and map them to genes. Such molecular quantitative trait locus mappings can be integrated with genome-wide association studies to make sense of the polygenic signal that underlies complex disease. Other resources that provide data on the 3-dimensional structure of chromatin and functional importance of specific genomic regions can be integrated similarly. In addition, mapped genes can then be tested for convergence in biological function, tissue, cell type, or developmental stage. In this review, we provide an overview of functional genomic resources and methods that can be used to interpret results from genome-wide association studies, and we discuss current challenges for biological understanding and future requirements to overcome them.

Original languageEnglish
Pages (from-to)41-53
Number of pages13
JournalBiological Psychiatry
Volume89
Issue number1
Early online date27 May 2020
DOIs
Publication statusPublished - 1 Jan 2021

Funding

This work was funded by The Netherlands Organization for Scientific Research (Grant No. NWO VICI 435–14–005 [to DP]) and NWO Gravitation: BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (Grant No. 024.004.012 [to DP]), a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057 [to DP]), and a VU University research fellowship (to EU).

FundersFunder number
Horizon 2020 Framework Programme834057
European Research Council
Vrije Universiteit Amsterdam
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO VICI 435–14–005, 024.004.012

    Keywords

    • Functional genomics
    • Gene-set analysis
    • Genome-wide association study
    • molQTL
    • Pathway analysis
    • Polygenicity

    Fingerprint

    Dive into the research topics of 'Emerging Methods and Resources for Biological Interrogation of Neuropsychiatric Polygenic Signal'. Together they form a unique fingerprint.

    Cite this