Steffens D C, Garrett M E, Soldano K L, McQuoid D R, Ashley-Koch A E, Potter G G
Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA.
Department of Medicine, Duke University Medicine Center, Durham, NC, USA.
Int Psychogeriatr. 2024 Nov;36(11):1021-1029. doi: 10.1017/S1041610220001143. Epub 2020 Jul 9.
This study sought to conduct a comprehensive search for genetic risk of cognitive decline in the context of geriatric depression.
A genome-wide association study (GWAS) analysis in the Neurocognitive Outcomes of Depression in the Elderly (NCODE) study.
Longitudinal, naturalistic follow-up study.
Older depressed adults, both outpatients and inpatients, receiving care at an academic medical center.
The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery was administered to the study participants at baseline and a minimum of twice within a subsequent 3-year period in order to measure cognitive decline. A GWAS analysis was conducted to identify genetic variation that is associated with baseline and change in the CERAD Total Score (CERAD-TS) in NCODE.
The GWAS of baseline CERAD-TS revealed a significant association with an intergenic single-nucleotide polymorphism (SNP) on chromosome 6, rs17662598, that surpassed adjustment for multiple testing ( = 3.7 × 10; false discovery rate = 0.0371). For each additional G allele, average baseline CERAD-TS decreased by 8.656 points. The most significant SNP that lies within a gene was rs11666579 in ( = 1.1 × 10). Each additional copy of the G allele was associated with an average decrease of baseline CERAD-TS of 4.829 points. is involved with processing docosahexaenoic acid (DHA), an endogenous neuroprotective compound in the brain. Decreased levels of DHA have been associated with the development of Alzheimer's disease. The most significant SNP associated with CERAD-TS decline over time was rs73240021 in ( = 1.1 × 10), a gene previously linked with deafness. However, none of the associations within genes survived adjustment for multiple testing.
Our GWAS of cognitive function and decline among individuals with late-life depression (LLD) has identified promising candidate genes that, upon replication in other cohorts of LLD, may be potential biomarkers for cognitive decline and suggests DHA supplementation as a possible therapy of interest.
本研究旨在全面探寻老年抑郁症患者认知功能衰退的遗传风险。
在老年人抑郁症神经认知结局（NCODE）研究中进行全基因组关联研究（GWAS）分析。
纵向、自然主义随访研究。
在一所学术医疗中心接受治疗的老年抑郁症门诊患者和住院患者。
在基线时以及在随后3年期间至少两次对研究参与者进行阿尔茨海默病注册协会（CERAD）神经心理成套测验，以测量认知功能衰退。进行GWAS分析以确定与NCODE中CERAD总分（CERAD-TS）的基线及变化相关的基因变异。
基线CERAD-TS的GWAS显示与6号染色体上的一个基因间单核苷酸多态性（SNP）rs17662598存在显著关联，该关联在多重检验校正后仍具有统计学意义（P = 3.7×10⁻⁶；错误发现率 = 0.0371）。每增加一个G等位基因，平均基线CERAD-TS降低8.656分。位于一个基因内的最显著SNP是rs11666579（P = 1.1×10⁻⁵）。G等位基因的每增加一个拷贝与基线CERAD-TS平均降低4.829分相关。该基因参与二十二碳六烯酸（DHA）的代谢，DHA是大脑中的一种内源性神经保护化合物。DHA水平降低与阿尔茨海默病的发生有关。与CERAD-TS随时间下降最显著相关的SNP是rs73240021（P = 1.1×10⁻⁵），该基因先前与耳聋有关。然而，基因内的所有关联在多重检验校正后均无统计学意义。
我们对老年抑郁症（LLD）患者认知功能及衰退的GWAS已鉴定出有前景的候选基因，在其他LLD队列中进行重复验证后，这些基因可能成为认知功能衰退的潜在生物标志物，并提示补充DHA可能是一种有意义的治疗方法。
