# Population-level and mechanistic dissection of 17q21 structural variant association with psychiatric traits

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $632,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Large-scale genetic studies have made tremendous progress identifying the heritable basis for many
neurodevelopmental, psychiatric disorders. However, connecting common genotypes to phenotypes -- and their
underlying biological mechanisms -- in the nervous system is often complicated by complex patterns of linkage
disequilibrium (LD) as well as the long-range action of genomic regulation. Common genetic variation within the
17q21.31 locus shows strong, highly pleiotropic genome-wide associations with several brain-related
phenotypes including neuroticism, PTSD, brain volume, educational attainment, as well as multiple
neurodegenerative disorders, among others. This locus, however, is among the most complex in the human
genome, as it is known to harbor at least 8 common, complex structural haplotypes, including a ~900 kb inversion
(“H2”) under positive selection and present in ~20% of Europeans. Consequently, the specific haplotypes
mediating these brain relevant trait-associations -- and the biological mechanisms through which this risk is
conferred -- remain unknown. This proposal leverages recently developed 17q21.31 haplotype-specific SNP
imputation panels to fully elucidate the “phenome-wide” impact of these common structural haplotypes on a wide
range of neurodevelopmental, psychiatric, cognitive, and neuroimaging phenotypes. In Aim 1, we interrogate
haplotype-specific neurodevelopmental trajectories in the iPSYCH case-cohort, comprising ~90k Danish
individuals with clinical and psychiatric diagnoses from nationwide medical registers. In Aim 2, we characterize
haplotype-specific associations with neuroimaging, psychiatric symptom, and cognitive phenotypes among up
to ~500k British 40-70 year old volunteers in the UK Biobank and in the ABCD Study, a community sample of
~10k 9-11 year olds in the US. In Aim 3, we interrogate the molecular impact of haplotypes on gene expression
and coexpression patterns in human brain across development. Finally, we perform single-cell RNA-seq and
ATAC-seq on primary human neural progenitor cell lines ascertained for distinct haplotypes, enabling direct
assessment of the allelic impact on developmental cell growth, gene expression, and chromatin accessibility.
Altogether, proposed studies will characterize the “phenome-wide” impact of common 17q21.31 complex
structural variation in the population and deconstruct the specific neurobiological mechanisms underlying these
broad associations with neurodevelopmental and psychiatric traits.

## Key facts

- **NIH application ID:** 10201458
- **Project number:** 5R01MH123922-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Michael Gandal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $632,000
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201458

## Citation

> US National Institutes of Health, RePORTER application 10201458, Population-level and mechanistic dissection of 17q21 structural variant association with psychiatric traits (5R01MH123922-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10201458. Licensed CC0.

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