Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands; Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts; Department of Psychiatry, Harvard Medical School, Boston, Massachusetts; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
Department of Biomedicine, Aarhus University, Aarhus, Denmark; The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark; Center for Genome Analysis and Personalized Medicine, Aarhus, Denmark; Bioinformatics Research Centre (BiRC), Aarhus, Denmark.
Biol Psychiatry. 2022 Jan 1;91(1):102-117. doi: 10.1016/j.biopsych.2021.02.972. Epub 2021 Mar 23.
Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.
We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.
Across disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10; rs73033497, p = 8.8 × 10; rs7914279, p = 6.4 × 10), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).
In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.
精神分裂症（SCZ）、重度抑郁症（MDD）和双相情感障碍（BIP）的发病率和/或表现存在性别差异。先前有证据表明，这些疾病的大脑异常存在共同的遗传风险和性别差异，这表明可能存在共同的性别依赖遗传风险。
我们利用来自 PGC（精神疾病基因组学联盟）和 iPSYCH 的 85735 例病例（33403 例 SCZ、19924 例 BIP 和 32408 例 MDD）和 109946 例对照，进行了迄今为止最大规模的全基因组基因型与性别的（G×S）交互作用风险分析。
在跨疾病的分析中，我们在包含 NKAIN2（rs117780815，p=3.2×10）的基因座上检测到全基因组显著的单核苷酸多态性与性别的相互作用，该基因座与钠/钾转运ATP 酶（三磷酸腺苷）酶相互作用，提示神经元兴奋性。另外三个基因座显示出跨疾病 G×S 相互作用的证据（p<1×10）（rs7302529，p=1.6×10；rs73033497，p=8.8×10；rs7914279，p=6.4×10），提示各种功能。基于基因的分析鉴定了跨疾病的 G×S 相互作用（p=8.97×10）与转录抑制剂 SLTM。在 SCZ 中最显著的是一个 MOCOS 基因座（rs11665282，p=1.5×10），提示血管内皮细胞。对 PGC-SCZ 数据集的二次分析检测到一个包含 IDO2 的基因座中的相互作用（rs13265509，p=1.1×10），IDO2 是一种色氨酸通路酶，具有免疫调节功能，与 SCZ、BIP 和 MDD 有关。途径富集分析检测到 MDD 中血管内皮生长因子受体信号转导相关基因的显著 G×S 相互作用（经错误发现率校正后，p<0.05）。
在迄今为止最大规模的情绪和精神病障碍全基因组 G×S 分析中，性别之间存在大量的遗传重叠。然而，在 SCZ、BIP 和 MDD 中，在变异体、基因和途径水平上，与神经元发育、免疫和血管功能相关的基因中，性别依赖性效应显著富集。
