---
title: "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’s disease: the Alzheimer’s Disease Genetics Consortium – Rajabli et al., 2025"
id: "8285"
type: "study"
slug: "sa000070"
published_at: "2025-08-05T16:07:06+00:00"
modified_at: "2026-03-26T16:40:12+00:00"
url: "https://dss.niagads.org/studies/sa000070/"
markdown_url: "https://dss.niagads.org/studies/sa000070.md"
excerpt: "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’s Disease (AD) Genetics Consortium (ADGC) to test..."
---

## Description

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’s 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* =2.4×10 -8) and *GRB14* (*P* =1.7×10 -8) in HIS), and *KIAA0825* (*P* =2.9×10 -8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with *P* adjusted =1.6×10 -4) and the classical complement pathway (*P* adjusted =1.3×10 -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.

## PI

Penelope Benchek  
 *Case Western Reserve University*

Gyungah R Jun  
 *Boston University*

Adam C Naj  
 *University of Pennsylvania*

Farid Rajabli  
 *University of Miami*

Christiane Reitz  
 *Columbia University*

Gerard Schellenberg  
 *University of Pennsylvania*

## Associated Datasets

- [NG00177 – ADGC Multi-Ancestry GWAS Meta-Analysis – Rajabli et al., 2025](https://dss.niagads.org/datasets/ng00177/) Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral backgrounds in genome-wide association studies (GWAS). We constructed and analyzed… [Learn more](https://dss.niagads.org/datasets/ng00177/)

## Grants

U01AG032984  
 RC2AG036528

## Acknowledgement

### Acknowledgment statement for any data distributed by NIAGADS:

Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689), funded by the National Institute on Aging.

### For investigators using 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's disease: the Alzheimer's Disease Genetics Consortium data:

The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; Samples from the National Cell Repository for Alzheimer’s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible; Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689); GCAD, U54 AG052427; NACC, U01 AG016976; NIA LOAD (Columbia University), U24AG056270; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, AG025259, R01 AG048927, RF1 AG057519, R01AG33193, R01 AG009029; Columbia University, P30AG066462, R01 AG072474, R01 AG067501; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, U01 AG006781, U01 HG004610, U01 HG006375, U01 HG008657; Indiana University, P30 AG10133, R01 AG009956, RC2 AG036650; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134, P30 AG062421; Mayo Clinic, P50 AG016574, R01 AG032990, KL2 RR024151; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616, 1RC2AG036502, 1R01AG035137; North Carolina A&T University, P20 MD000546, R01 AG28786-01A1; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG030146, R01 AG01101, RC2 AG036650, R01 AG22018; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Kentucky, P30 AG028383, AG05144; University of Michigan, P50 AG008671, P30 AG053760; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG030653, P50 AG041718, P50 AG064877, P30 AG066468; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG070864, AG052410, AG074527 and U01 AG058654, AG057659, AG062943, AG066767, AG076482 AND U19 AG074865; University of Washington and Kaiser Foundation Research Institute, P50 AG005136, R01 AG042437, P30 AG066509, U19 AG066567; University of Wisconsin, P50 AG033514; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991, P01 AG026276. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline. Support was also from the Alzheimer’s Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147), the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program, and BrightFocus Foundation (M.P.-V., A2111048). P.S.G.-H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG041232 to AJM and MJH, The Banner Alzheimer’s Foundation, The Johnnie B. Byrd Sr. Alzheimer’s Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council),South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE), Alzheimer’s Research Trust (ART), BRACE, Alzheimer's Brain Bank UK, and Development and Alumni Relations (DARO) Office, as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. ADNI data collection and sharing was funded by the National Institutes of Health Grant U01 AG024904 and Department of Defense award number W81XWH-12-2-0012. Funding for Saarland University was provided by the German Federal Ministry of Education and Research (BMBF), grant number 01GS08125 to Matthias Riemenschneider. ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Additional salary and analytical support were provided by NIA grants R01 AG054060 and RF1 AG061351. We thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-officio ADGC members.

## Publications

- Naj AC. **Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.***Nature genetics. 2011 May.*[PubMed link](https://pubmed.ncbi.nlm.nih.gov/21460841/)
- Kunkle BW. **Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.***Nature genetics. 2019 Mar.*[PubMed link](https://pubmed.ncbi.nlm.nih.gov/30820047/)
- Rajabli F. **Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.***Genome biology. 2025 Jul 17.*[PubMed link](https://pubmed.ncbi.nlm.nih.gov/40676597/)