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Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA.
The John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA.
Genome Biol. 2025 Jul 17;26(1):210. doi: 10.1186/s13059-025-03564-z.
Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis.
We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14).
Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.
在全基因组关联研究（GWAS）中，有限的祖先多样性削弱了我们检测在主要非欧洲祖先背景的祖先群体中更普遍的风险变异的能力。我们构建并分析了阿尔茨海默病遗传学联盟（ADGC）中的一个多祖先GWAS数据集，以检测新的共享和特定人群的晚发性阿尔茨海默病（LOAD）易感位点，并评估37382名非西班牙裔白人（NHW）、6728名非裔美国人、8899名西班牙裔（HIS）和3232名东亚个体的潜在遗传结构，先进行祖先内固定效应荟萃分析，然后进行跨祖先随机效应荟萃分析。
我们鉴定出13个具有跨人群关联的位点，包括CR1、BIN1、TREM2、CD2AP、PTK2B、CLU、SHARPIN、MS4A6A、PICALM、ABCA7、APOE附近的已知位点，以及11p12（LRRC4C）和12q24.13（LHX5-AS1）处两个先前未报道的新位点。我们还在HIS人群中PTPRK和GRB14附近以及NHW人群中KIAA0825附近鉴定出三个具有全基因组显著性的特定人群位点。通路分析涉及多个淀粉样蛋白调节通路和经典补体通路。我们新位点附近的基因在神经元发育（LRRC4C、LHX5-AS1和PTPRK）和胰岛素受体活性调节（GRB14）中具有已知作用。
通过跨人群GWAS荟萃分析，我们在LRRC4C和LHX5-AS1附近鉴定出了新的LOAD易感位点，这两个位点在神经元发育中均具有已知作用，以及几个新的人群特异性位点。反映了GWAS中不同祖先的强大作用，我们在仅占首次观察到该位点的NHW GWAS研究样本量13.7%（n = 409589）的样本中检测到了SHARPIN位点。继续扩展到更大的多祖先研究将为进一步阐明晚发性阿尔茨海默病的基因组学提供更大的助力。
