Investigating the genetic relationship between depression symptoms and Alzheimer's Disease in clinically diagnosed and proxy cases
Investigating the genetic relationship between depression symptoms and Alzheimer's Disease in clinically diagnosed and proxy cases
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在临床诊断和代理病例中调查抑郁症状与阿尔茨海默病之间的遗传关系
DOI：
10.1101/2023.06.05.23290588
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Gilchrist L
中科院分区：
文献类型：
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作者：
Gilchrist L
抑郁症是阿尔茨海默病（AD）后期发展的一个危险因素，但其遗传关系的证据是混合的。评估抑郁症症状特异性遗传关联可能会更好地阐明这种关系。使用来自英国生物库，GLAD研究和BACT的数据，我们对患者健康问卷（PHQ-9）（GWAS等效N：224，535 - 308，421）的9个抑郁症症状项目及其总分进行了最大的全基因组荟萃分析（GWAS）。然后，我们评估了全球和当地的遗传相关性和统计共定位之间的抑郁症/抑郁症症状和AD在六个AD GWAS与不同比例的临床和代理（家族史）的情况下确定。我们使用孟德尔随机化（MR）评估双向因果关系，并在三个临床AD队列中测试抑郁/抑郁症状多基因风险评分（PRS）对AD病例/对照状态的预测效用。我们的GWAS荟萃分析确定了10种抑郁症状表型中的37个基因组风险位点。在抑郁/抑郁症状与AD之间进行的72项总体遗传相关性检验中，20项在pFDR≤ 0.05时具有显著性。其中只有1例被确定为AD GWAS，仅包含临床病例。在14个位点上检测到局部遗传相关。在这些位点未发现统计共定位，但在多种抑郁症表型与临床仅AD和临床+代理AD之间的跨膜蛋白106 B（TMEM 106 B）区域发现了统计共定位。MR和PRS分析并没有产生显着的结果后，多次测试correction.Our的研究结果并没有表现出因果作用的抑郁症/抑郁症症状的AD，并建议抑郁症和AD之间的遗传重叠以前的证据可能是由包括基于家族史的代理病例/控制。然而，TMEM 106 B的共定位识别需要进一步研究。
Depression is a risk factor for the later development of Alzheimer’s disease (AD), but evidence for their genetic relationship is mixed. Assessing depression symptom specific genetic associations may better clarify this relationship.Using data from the UK Biobank, the GLAD Study and PROTECT, we performed the largest genome-wide meta-analyses (GWAS) of the nine depression symptom items, plus their sum score, on the Patient Health Questionnaire (PHQ-9) (GWAS equivalent N: 224,535–308,421). We then assessed global and local genetic correlations and statistical colocalisation between depression/depression symptoms and AD across six AD GWAS with varying proportions of clinical and proxy (family history) case ascertainment. We assessed bi-directional causal associations using Mendelian randomisation (MR) and tested the predictive utility of depression/depression symptom polygenic risk scores (PRS) for AD case/control status in three clinical AD cohorts.Our GWAS meta-analyses identified 37 genomic risk loci across the ten depression symptom phenotypes. Of the 72 global genetic correlation tests conducted between depression/depression symptoms and AD, 20 were significant at pFDR≤ 0.05. Only one of these was identified with AD GWAS containing clinical-only cases. Local genetic correlations were detected at 14 loci. Statistical colocalisation was not identified at these loci but was identified in the region of transmembrane protein 106B (TMEM106B) between multiple depression phenotypes and both clinical-only and clinical+proxy AD. MR and PRS analyses did not yield significant results after multiple testing correction.Our findings do not demonstrate a causal role of depression/depression symptoms on AD and suggest that previous evidence of genetic overlap between depression and AD may be driven by the inclusion of family-history-based proxy cases/controls. However, the identification of colocalisation at TMEM106B warrants further investigation.