The Genetic Architecture of Amygdala Nuclei

Mary S Mufford; Dennis van der Meer; Tobias Kaufmann; Oleksandr Frei; Raj Ramesar; Paul M Thompson; Neda Jahanshad; Rajendra A Morey; Ole A Andreassen; Dan J Stein; Shareefa Dalvie

doi:10.1016/j.biopsych.2023.06.022

The Genetic Architecture of Amygdala Nuclei

Biol Psychiatry. 2024 Jan 1;95(1):72-84. doi: 10.1016/j.biopsych.2023.06.022. Epub 2023 Jun 29.

Authors

Affiliations

¹ South African Medical Research Council Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; Global Initiative for Neuropsychiatric Genetics Education in Research program, Harvard T.H. Chan School of Public Health and the Stanley Center for Psychiatric Research at the Broad Institute of Harvard and MIT, Boston, Massachusetts; South African Medical Research Council Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa. Electronic address: [email protected].
² Norwegian Centre for Mental Disorders Research Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway; School of Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
³ Norwegian Centre for Mental Disorders Research Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Psychiatry and Psychotherapy, Tübingen Center for Mental Health, University of Tübingen, Tübingen, Germany.
⁴ Norwegian Centre for Mental Disorders Research Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway.
⁵ South African Medical Research Council Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
⁶ Imaging Genetics Center, Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of the University of Southern California, Marina del Rey, California.
⁷ Duke-UNC Brain Imaging and Analysis Center, Duke University, Durham, North Carolina.
⁸ Norwegian Centre for Mental Disorders Research Centre, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway; KG Jebsen Centre for Neurodevelopmental Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁹ South African Medical Research Council Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.

PMID: 37391117
DOI: 10.1016/j.biopsych.2023.06.022

Abstract

Background: Whereas genetic variants influencing total amygdala volume have been identified, the genetic architecture of its distinct nuclei has yet to be explored. We aimed to investigate whether increased phenotypic specificity through nuclei segmentation aids genetic discoverability and elucidates the extent of shared genetic architecture and biological pathways with related disorders.

Methods: T1-weighted brain magnetic resonance imaging scans (N = 36,352, 52% female) from the UK Biobank were segmented into 9 amygdala nuclei with FreeSurfer (version 6.1). Genome-wide association analyses were performed on the entire sample, a European-only subset (n = 31,690), and a generalization (transancestry) subset (n = 4662). We estimated single nucleotide polymorphism-based heritability; derived polygenicity, discoverability, and power estimates; and investigated genetic correlations and shared loci with psychiatric disorders.

Results: The heritability of the nuclei ranged from 0.17 to 0.33. Across the whole amygdala and the nuclei volumes, we identified 28 novel genome-wide significant (p_adj < 5 × 10^-9) loci in the European analysis, with significant en masse replication for the whole amygdala and central nucleus volumes in the generalization analysis, and we identified 10 additional candidate loci in the combined analysis. The central nucleus had the highest statistical power for discovery. The significantly associated genes and pathways showed unique and shared effects across the nuclei, including immune-related pathways. Shared variants were identified between specific nuclei and autism spectrum disorder, Alzheimer's disease, Parkinson's disease, bipolar disorder, and schizophrenia.

Conclusions: Through investigation of amygdala nuclei volumes, we have identified novel candidate loci in the neurobiology of amygdala volume. These nuclei volumes have unique associations with biological pathways and genetic overlap with psychiatric disorders.

Keywords: Amygdala nuclei; Genetics; Heritability; Psychiatry; Structural MRI; Trauma.

MeSH terms

Amygdala / diagnostic imaging
Autism Spectrum Disorder* / genetics
Bipolar Disorder* / diagnostic imaging
Bipolar Disorder* / genetics
Brain
Female
Genetic Loci
Genetic Predisposition to Disease / genetics
Genome-Wide Association Study
Humans
Male
Polymorphism, Single Nucleotide / genetics