Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies LRRC4C, LHX5-AS1 and nominates ancestry-specific loci PTPRK, GRB14, and KIAA0825 as novel risk loci for Alzheimer disease: the Alzheimer Disease Genetics Consortium
Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies LRRC4C, LHX5-AS1 and nominates ancestry-specific loci PTPRK, GRB14, and KIAA0825 as novel risk loci for Alzheimer disease: the Alzheimer Disease Genetics Consortium
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DOI：
10.1101/2023.07.06.23292311
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发表时间：
2023-07
期刊：
影响因子：
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通讯作者：
F. Rajabli;Penelope Benchek;G. Tosto;Nicholas A. Kushch;Jin Sha;Katrina Bazemore;Congcong Zhu;
中科院分区：
文献类型：
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作者：
F. Rajabli;Penelope Benchek;G. Tosto;Nicholas A. Kushch;Jin Sha;Katrina Bazemore;Congcong Zhu;
有限的祖先多样性削弱了我们在全基因组关联研究（GWAS）中检测非欧洲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（AD）遗传学联盟（ADGC）中的多祖先GWAS数据集，以测试新的共享和祖先特异性AD易感基因座，并评估37，382名非西班牙裔白色（NHW），6，728名非洲裔美国人，8，899名西班牙裔（HIS）和3，232名东亚个体的潜在遗传结构。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。我们确定了13个具有跨祖先关联的基因座，包括位于或靠近CR 1、BIN 1、TREM 2、CD 2AP、PTK 2B、CLU、SHARPIN、MS 4A 6A、PICALM、ABCA 7、APOE的已知基因座以及先前未报道的位于11 p12（LRRC 4C）和12q24.13（LHX 5-AS 1）的两个新基因座。为了反映GWAS中不同祖先的力量，我们使用原始发现单祖先GWAS（n= 788，989）样本量的7.1%观察SHARPIN基因座。我们还鉴定了三个GWS祖先特异性基因座（在HIS中为PTR 4（P=2.4E10-8）和GRB 14（P=1.7E10-8））和KIAA 0825（在NHW中为P=2.9E10-8）处/附近。通路分析涉及多个淀粉样蛋白调节通路（最强，P调节=1.6E10-4）和经典补体通路（P调节=1.3E10-3）。在我们的新基因座处/附近的基因在神经元发育（LRRC 4C、LHX 5-AS 1和PTF 1）和胰岛素受体活性调节（GRB 14）中具有已知的作用。这些发现为使用传统上代表性不足的人群进行基因发现提供了令人信服的支持，即使样本量较小。
Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry 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). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near (PTPRK (P=2.4E10-8) and GRB14 (P=1.7E10-8) in HIS), and KIAA0825 (P=2.9E10-8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with Padjusted=1.6E10-4) and the classical complement pathway (Padjusted=1.3E10-3). Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.