杏仁核核团的遗传结构。

The Genetic Architecture of Amygdala Nuclei.

机构信息

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.

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.

出版信息

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

DOI:10.1016/j.biopsych.2023.06.022

PMID:37391117

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 < 5 × 10) 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.

摘要

背景

虽然已经确定了影响总杏仁核体积的遗传变异，但杏仁核不同核团的遗传结构尚未得到探索。我们旨在研究通过核团分割是否能提高表型特异性，从而帮助遗传发现，并阐明与相关疾病共享遗传结构和生物学途径的程度。

方法

使用 FreeSurfer（版本 6.1）对英国生物库中的 36352 名参与者（52%为女性）的 T1 加权脑磁共振成像扫描进行分割，得到 9 个杏仁核核团。对整个样本、仅欧洲人样本（n=31690）和泛化（跨种族）样本（n=4662）进行全基因组关联分析。我们估计了基于单核苷酸多态性的遗传力；推导了多基因性、可发现性和功效估计；并研究了遗传相关性和与精神疾病的共享基因座。

结果

核团的遗传力范围从 0.17 到 0.33。在整个杏仁核和核团体积中，我们在欧洲分析中确定了 28 个新的全基因组显著（p<5×10）位点，在泛化分析中，整个杏仁核和中央核体积的整体复制具有显著意义，并且在联合分析中确定了另外 10 个候选基因座。中央核的发现统计能力最高。显著相关的基因和途径在核团之间显示出独特和共享的影响，包括免疫相关途径。在特定核团和自闭症谱系障碍、阿尔茨海默病、帕金森病、双相情感障碍和精神分裂症之间确定了共享变异。