Abstract:
Background
Genome-wide association studies have discovered blocks of common variants—likely transcriptional-regulatory—associated
with major depressive disorder (MDD), though the functional subset and their biological
impacts remain unknown. Likewise, why depression occurs in females more frequently
than males is unclear. We therefore tested the hypothesis that risk-associated functional
variants interact with sex and produce greater impact in female brains.
Methods
We developed techniques to directly measure regulatory variant activity and sex interactions
using massively parallel reporter assays (MPRAs) in the mouse brain in vivo, in a cell type-specific manner, and applied these approaches to measure activity
of >1,000 variants from >30 MDD loci.
Results
We identified extensive sex-by-allele effects in mature hippocampal neurons, suggesting
sex-differentiated impacts of genetic risk may underlie sex bias in disease. Unbiased
informatics approaches indicated that functional MDD variants recurrently disrupt
a number of transcription factor binding motifs, including those of sex hormone receptors.
We confirmed a role for the latter by performing MPRAs in neonatal mice on the day
of birth (during a sex-differentiating hormone surge) and hormonally-quiescent juveniles.
Conclusions
Our study provides novel insights into the influence of age, biological sex, and cell
type on regulatory variant function, and provides a framework for in vivo parallel assays to functionally define interactions between organismal variables
like sex and regulatory variation. Moreover, we experimentally demonstrate that a
portion the sex differences seen in MDD occurrence may be a product of sex-differentiated
effects at associated regulatory variants.
Keywords
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Article info
Publication history
Accepted:
February 7,
2023
Received in revised form:
January 19,
2023
Received:
May 3,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
One-Sentence Summary: Massively parallel assays in vivo identified extensive functional and sex-interacting common variants in depression risk loci.
References and Notes
Funding:
National Institutes of Mental Health (NIMH) grant 5F30MH116654 (BM)
NIMH grant 1R01MH116999 (JDD)
Simons Foundation grant 571009 (JDD)
Author contributions:
Conceptualization: BM, JDD, DS
Methodology: BM, DS, JDD
Investigation: BM, DS
Visualization: BM, DS
Funding acquisition: BM, JDD
Project administration: BM, JDD
Supervision: BM, JDD
Writing – original draft: BM, DS, JDD
Writing – review & editing: BM, JDD, DS
Competing interests: The authors report no biomedical financial interests or potential conflicts of interest.
Data and materials availability: The annotation of library SNPs performed at the time of design are available at https://bitbucket.org/jdlabteam/n2a_atra_mdd_mpra_paper/src/master/Library%20Design%20Epigenomic%20Annotations/. Code is available at https://bitbucket.org/jdlabteam/paper-resources-mdd-in-vivo-mpras/src. Raw sequencing files and tabulated barcode counts per sample are available through GEO accession GSE186348 with reviewer token evabumkctpsltut. Outside datasets used for annotation are detailed in Supplementary Materials.
Identification
Copyright
© 2023 Published by Elsevier Inc on behalf of Society of Biological Psychiatry.
