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
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2023 |
|---|---|
| Enthalten in: |
medRxiv : the preprint server for health sciences - (2023) vom: 08. Juli |
| Sprache: |
Englisch |
|---|
| Links: |
|---|
| Themen: |
|---|
| Anmerkungen: |
Date Revised 01.05.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.1101/2023.07.06.23292311 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM359621791 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM359621791 | ||
| 003 | DE-627 | ||
| 005 | 20240501232032.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2023.07.06.23292311 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1394.xml |
| 035 | |a (DE-627)NLM359621791 | ||
| 035 | |a (NLM)37461624 | ||
| 035 | |a (PII)2023.07.06.23292311 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Rajabli, Farid |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a 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 |b the Alzheimer's Disease Genetics Consortium |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 01.05.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Preprint | |
| 700 | 1 | |a Benchek, Penelope |e verfasserin |4 aut | |
| 700 | 1 | |a Tosto, Giuseppe |e verfasserin |4 aut | |
| 700 | 1 | |a Kushch, Nicholas |e verfasserin |4 aut | |
| 700 | 1 | |a Sha, Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Bazemore, Katrina |e verfasserin |4 aut | |
| 700 | 1 | |a Zhu, Congcong |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Wan-Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Haut, Jacob |e verfasserin |4 aut | |
| 700 | 1 | |a Hamilton-Nelson, Kara L |e verfasserin |4 aut | |
| 700 | 1 | |a Wheeler, Nicholas R |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Farrell, John J |e verfasserin |4 aut | |
| 700 | 1 | |a Grunin, Michelle A |e verfasserin |4 aut | |
| 700 | 1 | |a Leung, Yuk Yee |e verfasserin |4 aut | |
| 700 | 1 | |a Kuksa, Pavel P |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Donghe |e verfasserin |4 aut | |
| 700 | 1 | |a Lucio da Fonseca, Eder |e verfasserin |4 aut | |
| 700 | 1 | |a Mez, Jesse B |e verfasserin |4 aut | |
| 700 | 1 | |a Palmer, Ellen L |e verfasserin |4 aut | |
| 700 | 1 | |a Pillai, Jagan |e verfasserin |4 aut | |
| 700 | 1 | |a Sherva, Richard M |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Yeunjoo E |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xiaoling |e verfasserin |4 aut | |
| 700 | 1 | |a Iqbal, Taha |e verfasserin |4 aut | |
| 700 | 1 | |a Pathak, Omkar |e verfasserin |4 aut | |
| 700 | 1 | |a Valladares, Otto |e verfasserin |4 aut | |
| 700 | 1 | |a Kuzma, Amanda B |e verfasserin |4 aut | |
| 700 | 1 | |a Abner, Erin |e verfasserin |4 aut | |
| 700 | 1 | |a Adams, Perrie M |e verfasserin |4 aut | |
| 700 | 1 | |a Aguirre, Alyssa |e verfasserin |4 aut | |
| 700 | 1 | |a Albert, Marilyn S |e verfasserin |4 aut | |
| 700 | 1 | |a Albin, Roger L |e verfasserin |4 aut | |
| 700 | 1 | |a Allen, Mariet |e verfasserin |4 aut | |
| 700 | 1 | |a Alvarez, Lisa |e verfasserin |4 aut | |
| 700 | 1 | |a Apostolova, Liana G |e verfasserin |4 aut | |
| 700 | 1 | |a Arnold, Steven E |e verfasserin |4 aut | |
| 700 | 1 | |a Asthana, Sanjay |e verfasserin |4 aut | |
| 700 | 1 | |a Atwood, Craig S |e verfasserin |4 aut | |
| 700 | 1 | |a Ayres, Gayle |e verfasserin |4 aut | |
| 700 | 1 | |a Baldwin, Clinton T |e verfasserin |4 aut | |
| 700 | 1 | |a Barber, Robert C |e verfasserin |4 aut | |
| 700 | 1 | |a Barnes, Lisa L |e verfasserin |4 aut | |
| 700 | 1 | |a Barral, Sandra |e verfasserin |4 aut | |
| 700 | 1 | |a Beach, Thomas G |e verfasserin |4 aut | |
| 700 | 1 | |a Becker, James T |e verfasserin |4 aut | |
| 700 | 1 | |a Beecham, Gary W |e verfasserin |4 aut | |
| 700 | 1 | |a Beekly, Duane |e verfasserin |4 aut | |
| 700 | 1 | |a Benitez, Bruno A |e verfasserin |4 aut | |
| 700 | 1 | |a Bennett, David |e verfasserin |4 aut | |
| 700 | 1 | |a Bertelson, John |e verfasserin |4 aut | |
| 700 | 1 | |a Bird, Thomas D |e verfasserin |4 aut | |
| 700 | 1 | |a Blacker, Deborah |e verfasserin |4 aut | |
| 700 | 1 | |a Boeve, Bradley F |e verfasserin |4 aut | |
| 700 | 1 | |a Bowen, James D |e verfasserin |4 aut | |
| 700 | 1 | |a Boxer, Adam |e verfasserin |4 aut | |
| 700 | 1 | |a Brewer, James |e verfasserin |4 aut | |
| 700 | 1 | |a Burke, James R |e verfasserin |4 aut | |
| 700 | 1 | |a Burns, Jeffrey M |e verfasserin |4 aut | |
| 700 | 1 | |a Buxbaum, Joseph D |e verfasserin |4 aut | |
| 700 | 1 | |a Cairns, Nigel J |e verfasserin |4 aut | |
| 700 | 1 | |a Cantwell, Laura B |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Chuanhai |e verfasserin |4 aut | |
| 700 | 1 | |a Carlson, Christopher S |e verfasserin |4 aut | |
| 700 | 1 | |a Carlsson, Cynthia M |e verfasserin |4 aut | |
| 700 | 1 | |a Carney, Regina M |e verfasserin |4 aut | |
| 700 | 1 | |a Carrasquillo, Minerva M |e verfasserin |4 aut | |
| 700 | 1 | |a Chasse, Scott |e verfasserin |4 aut | |
| 700 | 1 | |a Chesselet, Marie-Francoise |e verfasserin |4 aut | |
| 700 | 1 | |a Chin, Nathaniel A |e verfasserin |4 aut | |
| 700 | 1 | |a Chui, Helena C |e verfasserin |4 aut | |
| 700 | 1 | |a Chung, Jaeyoon |e verfasserin |4 aut | |
| 700 | 1 | |a Craft, Suzanne |e verfasserin |4 aut | |
| 700 | 1 | |a Crane, Paul K |e verfasserin |4 aut | |
| 700 | 1 | |a Cribbs, David H |e verfasserin |4 aut | |
| 700 | 1 | |a Crocco, Elizabeth A |e verfasserin |4 aut | |
| 700 | 1 | |a Cruchaga, Carlos |e verfasserin |4 aut | |
| 700 | 1 | |a Cuccaro, Michael L |e verfasserin |4 aut | |
| 700 | 1 | |a Cullum, Munro |e verfasserin |4 aut | |
| 700 | 1 | |a Darby, Eveleen |e verfasserin |4 aut | |
| 700 | 1 | |a Davis, Barbara |e verfasserin |4 aut | |
| 700 | 1 | |a De Jager, Philip L |e verfasserin |4 aut | |
| 700 | 1 | |a DeCarli, Charles |e verfasserin |4 aut | |
| 700 | 1 | |a DeToledo, John |e verfasserin |4 aut | |
| 700 | 1 | |a Dick, Malcolm |e verfasserin |4 aut | |
| 700 | 1 | |a Dickson, Dennis W |e verfasserin |4 aut | |
| 700 | 1 | |a Dombroski, Beth A |e verfasserin |4 aut | |
| 700 | 1 | |a Doody, Rachelle S |e verfasserin |4 aut | |
| 700 | 1 | |a Duara, Ranjan |e verfasserin |4 aut | |
| 700 | 1 | |a Ertekin-Taner, NIlüfer |e verfasserin |4 aut | |
| 700 | 1 | |a Evans, Denis A |e verfasserin |4 aut | |
| 700 | 1 | |a Faber, Kelley M |e verfasserin |4 aut | |
| 700 | 1 | |a Fairchild, Thomas J |e verfasserin |4 aut | |
| 700 | 1 | |a Fallon, Kenneth B |e verfasserin |4 aut | |
| 700 | 1 | |a Fardo, David W |e verfasserin |4 aut | |
| 700 | 1 | |a Farlow, Martin R |e verfasserin |4 aut | |
| 700 | 1 | |a Fernandez-Hernandez, Victoria |e verfasserin |4 aut | |
| 700 | 1 | |a Ferris, Steven |e verfasserin |4 aut | |
| 700 | 1 | |a Foroud, Tatiana M |e verfasserin |4 aut | |
| 700 | 1 | |a Frosch, Matthew P |e verfasserin |4 aut | |
| 700 | 0 | |a et al |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |t medRxiv : the preprint server for health sciences |d 2020 |g (2023) vom: 08. Juli |w (DE-627)NLM310900166 |7 nnns |
| 773 | 1 | 8 | |g year:2023 |g day:08 |g month:07 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2023.07.06.23292311 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |j 2023 |b 08 |c 07 | ||