Talyansky Seth, Guen Yann Le, Kasireddy Nandita, Belloy Michael E, Greicius Michael D
Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
Institut du Cerveau - Paris Brain Institute - ICM, Paris, France.
medRxiv. 2023 Jul 20:2023.04.21.23288938. doi: 10.1101/2023.04.21.23288938.
Lewy body (LB) pathology commonly occurs in individuals with Alzheimer's disease (AD) pathology. However, it remains unclear which genetic risk factors underlie AD pathology, LB pathology, or AD-LB co-pathology. Notably, whether - 4 affects risk of LB pathology independently from AD pathology is controversial. We adapted criteria from the literature to classify 4,985 subjects from the National Alzheimer's Coordinating Center (NACC) and the Rush University Medical Center as AD-LB co-pathology (AD LB ), sole AD pathology (AD LB ), sole LB pathology (AD LB ), or no pathology (AD LB ). We performed a meta-analysis of a genome-wide association study (GWAS) per subpopulation (NACC/Rush) for each disease phenotype compared to the control group (AD LB ), and compared the AD LB to AD LB groups. - 4 was significantly associated with risk of AD LB and AD LB compared to AD LB . However, - 4 was not associated with risk of AD LB compared to AD LB or risk of AD LB compared to AD LB . Associations at the locus exhibited qualitatively similar results. These results suggest that - 4 is a risk factor for AD pathology, but not for LB pathology when decoupled from AD pathology. The same holds for risk variants. These findings, in the largest AD-LB neuropathology GWAS to date, distinguish the genetic risk factors for sole and dual AD-LB pathology phenotypes. Our GWAS meta-analysis summary statistics, derived from phenotypes based on postmortem pathologic evaluation, may provide more accurate disease-specific polygenic risk scores compared to GWAS based on clinical diagnoses, which are likely confounded by undetected dual pathology and clinical misdiagnoses of dementia type.
路易体（LB）病理常见于患有阿尔茨海默病（AD）病理的个体中。然而，尚不清楚哪些遗传风险因素是AD病理、LB病理或AD-LB共同病理的基础。值得注意的是，-4是否独立于AD病理影响LB病理风险存在争议。我们采用文献中的标准，将来自国家阿尔茨海默病协调中心（NACC）和拉什大学医学中心的4985名受试者分类为AD-LB共同病理（AD LB ）、单纯AD病理（AD LB ）、单纯LB病理（AD LB ）或无病理（AD LB ）。我们对每个疾病表型的每个亚组（NACC/拉什）与对照组（AD LB ）进行全基因组关联研究（GWAS）的荟萃分析，并比较AD LB 组与AD LB 组。与AD LB 相比，-4与AD LB 和AD LB 的风险显著相关。然而，与AD LB 相比，-4与AD LB 的风险无关，与AD LB 相比，-4与AD LB 的风险也无关。该位点的关联结果在性质上相似。这些结果表明，-4是AD病理的风险因素，但与AD病理分离时不是LB病理的风险因素。对于风险变异也是如此。在迄今为止最大的AD-LB神经病理学GWAS中，这些发现区分了单纯和双重AD-LB病理表型的遗传风险因素。我们基于死后病理评估的表型得出的GWAS荟萃分析总结统计数据，与基于临床诊断的GWAS相比，可能提供更准确的疾病特异性多基因风险评分，后者可能因未检测到的双重病理和痴呆类型的临床误诊而混淆。
