Campbell Megan L, Dalvie Shareefa, Shadrin Alexey, van der Meer Dennis, O'Connell Kevin, Frei Oleksander, Andreassen Ole A, Stein Dan J, Rokicki Jaroslav
Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
Global Initiative for Neuropsychiatric Genetics Education in Research (GINGER), Harvard, T.H. Chan School of Public Health, Boston, MA, USA.
Acta Neuropsychiatr. 2023 Aug 24;37:e23. doi: 10.1017/neu.2023.32.
The corpus callosum (CC) is a brain structure with a high heritability and potential role in psychiatric disorders. However, the genetic architecture of the CC and the genetic link with psychiatric disorders remain largely unclear. We investigated the genetic architectures of the volume of the CC and its subregions and the genetic overlap with psychiatric disorders.
We applied multivariate genome-wide association study (GWAS) to genetic and T1-weighted magnetic resonance imaging (MRI) data of 40,894 individuals from the UK Biobank, aiming to boost genetic discovery and to assess the pleiotropic effects across volumes of the five subregions of the CC (posterior, mid-posterior, central, mid-anterior and anterior) obtained by FreeSurfer 7.1. Multivariate GWAS was run combining all subregions, co-varying for relevant variables. Gene-set enrichment analyses were performed using MAGMA. Linkage disequilibrium score regression (LDSC) was used to determine Single nucleotide polymorphism (SNP)-based heritability of total CC volume and volumes of its subregions as well as their genetic correlations with relevant psychiatric traits.
We identified 70 independent loci with distributed effects across the five subregions of the CC ( < 5 × 10). Additionally, we identified 33 significant loci in the anterior subregion, 23 in the mid-anterior, 29 in the central, 7 in the mid-posterior and 56 in the posterior subregion. Gene-set analysis revealed 156 significant genes contributing to volume of the CC subregions ( < 2.6 × 10). LDSC estimated the heritability of CC to ( = 0.38, SE = 0.03) and subregions ranging from 0.22 (SE = 0.02) to 0.37 (SE = 0.03). We found significant genetic correlations of total CC volume with bipolar disorder (BD, = -0.09, SE = 0.03; = 5.9 × 10) and drinks consumed per week ( = -0.09, SE = 0.02; = 4.8 × 10), and volume of the mid-anterior subregion with BD ( = -0.12, SE = 0.02; = 2.5 × 10), major depressive disorder (MDD) ( = -0.12, SE = 0.04; = 3.6 × 10), drinks consumed per week ( = -0.13, SE = 0.04; = 1.8 × 10) and cannabis use ( = -0.09, SE = 0.03; = 8.4 × 10).
Our results demonstrate that the CC has a polygenic architecture implicating multiple genes and show that CC subregion volumes are heritable. We found that distinct genetic factors are involved in the development of anterior and posterior subregions, consistent with their divergent functional specialisation. Significant genetic correlation between volumes of the CC and BD, drinks per week, MDD and cannabis consumption subregion volumes with psychiatric traits is noteworthy and deserving of further investigation.
胼胝体（CC）是一种遗传性较高的脑结构，在精神疾病中可能发挥作用。然而，CC的遗传结构以及与精神疾病的遗传联系仍不清楚。我们研究了CC及其亚区体积的遗传结构以及与精神疾病的遗传重叠情况。
我们对来自英国生物银行的40894名个体的基因和T1加权磁共振成像（MRI）数据应用多变量全基因组关联研究（GWAS），旨在促进基因发现，并评估通过FreeSurfer 7.1获得的CC五个亚区（后部、中后部、中部、中前部和前部）体积的多效性效应。结合所有亚区进行多变量GWAS分析，并对相关变量进行协变量调整。使用MAGMA进行基因集富集分析。连锁不平衡评分回归（LDSC）用于确定基于单核苷酸多态性（SNP）的CC总体积及其亚区体积的遗传力，以及它们与相关精神特质的遗传相关性。
我们在CC的五个亚区中鉴定出70个具有分布效应的独立基因座（P<5×10⁻⁸）。此外，我们在前部亚区鉴定出33个显著基因座，中前部23个，中部29个，中后部7个，后部56个。基因集分析揭示了156个对CC亚区体积有贡献的显著基因（P<2.6×10⁻⁸）。LDSC估计CC的遗传力为h² = 0.38（标准误 = 0.03），亚区遗传力范围为0.22（标准误 = 0.02）至0.37（标准误 = 0.03）。我们发现CC总体积与双相情感障碍（BD，r = -0.09，标准误 = 0.03；P = 5.9×10⁻⁵）和每周饮酒量（r = -0.09，标准误 = 0.02；P = 4.8×10⁻⁵）之间存在显著遗传相关性，中前部亚区体积与BD（r = -0.12，标准误 = 0.02；P = 2.5×10⁻⁵）、重度抑郁症（MDD）（r = -0.12，标准误 = 0.04；P = 3.6×10⁻⁴）、每周饮酒量（r = -0.13，标准误 = 0.04；P = 1.8×10⁻⁴）和大麻使用（r = -0.09，标准误 = 0.03；P = 8.4×10⁻⁵）之间存在显著遗传相关性。
我们的结果表明，CC具有涉及多个基因的多基因结构，且CC亚区体积具有遗传性。我们发现不同的遗传因素参与了前部和后部亚区的发育，这与其不同的功能特化一致。CC体积与BD、每周饮酒量、MDD以及大麻使用之间的显著遗传相关性以及亚区体积与精神特质之间的相关性值得进一步研究。
