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

The Genetic Architecture of Amygdala Nuclei

Mary S Mufford  1 , Dennis van der Meer  2 , Tobias Kaufmann  3 , Oleksandr Frei  4 , Raj Ramesar  5 , Paul M Thompson  6 , Neda Jahanshad  6 , Rajendra A Morey  7 , Ole A Andreassen  8 , Dan J Stein  9 , Shareefa Dalvie  5
Affiliations

The Genetic Architecture of Amygdala Nuclei

Mary S Mufford et al. Biol Psychiatry. .

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 (padj < 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.

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Conflict of interest statement

OAA reported grants from Stiftelsen Kristian Gerhard Jebsen, South-East Regional Health Authority, Research Council of Norway, and European Union’s Horizon 2020 during the conduct of the study, as well as personal fees from HealthLytix (stock options), Lundbeck (speaker’s honorarium), and Sunovion (speaker’s honorarium) outside the submitted work. AMD reported grants from the National Institutes of Health outside the submitted work, had a patent for US7324842 licensed to Siemens Healthineers, is a founder of and holds equity in Cortechs Labs and serves on its scientific advisory board; is a member of the scientific advisory board of Human Longevity, is a member of the scientific advisory board of HealthLytix, and receives funding through a research agreement with GE Healthcare. All other authors report no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1.
Figure 1.
Segmentation of the amygdala nuclei. (A) Using FreeSurfer (version 6.1), the amygdala was segmented into 9 nuclei: anterior amygdaloid area = yellow, cortico-amygdaloid transition area = dark blue, basal = red, lateral = light blue, accessory basal = orange, central = purple, medial = green. The cortical and paralaminar nuclei are not shown here. (B) Structural T1 scan provided for reference. Images provided by Morey et al. (12).
Figure 2.
Figure 2.
Correlation matrix of the volume estimates for the nuclei as well as several other subcortical regions of interest. (A) All correlations are multiplied by a factor of 100. The volumetric correlations are shown in the lower triangle of the matrix (green-orange), the heritability estimates on the diagonal, and the genetic correlations in the upper triangle (blue-red). This heatmap was generated using corrplot (2) in R (version 3.6). (B) The order, indicated by the dendrogram on the left, was determined by hierarchical clustering using Ward’s D2 method. AAA, anterior amygdaloid area; ACC, accessory basal nucleus; BAS, basal nucleus; CAT, corticoamygdaloid transition area; CEN, central nucleus; COR, cortical nucleus; LAT, lateral nucleus; MED, medial nucleus; PAR, paralaminar nucleus.
Figure 3.
Figure 3.
Heatmap of the estimated proportion of shared variants between amygdala nuclei volumes. The heatmap illustrates the Dice coefficients between the amygdala nuclei volumes as determined by bivariate MiXeR, which indicate what proportion of the nuclei on the x-axis is shared with the nuclei on the y-axis. The order in which the nuclei appear on the heatmap was determined by hierarchical clustering using Ward’s D2 method. This heatmap was generated using corrplot (2) in R (version 3.6). AAA, anterior amygdaloid area; ACC, accessory basal nucleus; BAS, basal nucleus; CAT, corticoamygdaloid transition area; CEN, central nucleus; COR, cortical nucleus; LAT, lateral nucleus; MED, medial nucleus; PAR, paralaminar nucleus; TOT, whole amygdala.
Figure 4.
Figure 4.
MiXeR power curves and model fit for all amygdala nuclei volumes from the European and combined analyses. (A) and (B) refer to the power curves for the whole amygdala and its nuclei for the European and combined analyses, respectively. This figure depicts the sample size required so that a given proportion of phenotypic variability is captured by significant SNPs for the nuclei volumes. Each curve on the plot represents a different nucleus, and the right-to-left curve is determined by decreasing discoverability. The proportion of phenotypic variance explained is shown in brackets next to the corresponding nucleus volume in the legend. AAA, anterior amygdaloid area; ACC, accessory basal nucleus; BAS, basal nucleus; CAT, corticoamygdaloid transition area; CEN, central nucleus; COR, cortical nucleus; LAT, lateral nucleus; MED, medial nucleus; PAR, paralaminar nucleus; SNP, single nucleotide polymorphism; TOT, whole amygdala.
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