A new risk locus on chromosome 1 is suggested by genome‐wide association study in Peruvians for Alzheimer disease
Background Increasing ethnic/ancestral diversity in genetic studies is critical for defining the genetic architecture of Alzheimer disease (AD). Amerindian (AI) populations are substantially underrepresented in AD genetic studies. The Peruvian (PE) population, with up to ∼80% of AI ancestry, provide...
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| Veröffentlicht in: | Alzheimer's & dementia 2023-12, Vol.19 (S12), p.n/a |
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| creator | Akgun, Bilcag Cornejo‐Olivas, Mario Custodio, Nilton Rajabli, Farid Soto‐Añari, Marcio F. Montesinos, Rosa Yang, Zikun Huaman, Basilio C. Reyes‐Dumeyer, Dolly Cedeno, Jeffrey A Rivero, Joe Mena, Pedro R. Adams, Larry D. Whitehead, Patrice Hamilton‐Nelson, Kara L. Rios‐Pinto, Julia Medina‐Colque, Angel Dalgard, Clifton L. Isasi, Rosario Cornejo‐Herrera, Ivan Illanes‐Manrique, Maryenela Ochoa‐Valle, Edward Sarapura‐Castro, Elison Mejía, Koni K. Milla‐Neyra, Karina Castro‐Suarez, Sheila Martin, Eden R. Griswold, Anthony J. McInerney, Katalina Cuccaro, Michael L. Vance, Jeffery M. Beecham, Gary W. Pericak‐Vance, Margaret A. Tosto, Giuseppe |
| description | Background
Increasing ethnic/ancestral diversity in genetic studies is critical for defining the genetic architecture of Alzheimer disease (AD). Amerindian (AI) populations are substantially underrepresented in AD genetic studies. The Peruvian (PE) population, with up to ∼80% of AI ancestry, provides a unique opportunity to assess the role of AI ancestry in AD. We performed the first genome‐wide association study (GWAS) in the PE population to identify novel AD susceptibility loci and characterize known AD genetic risk loci.
Method
The PE dataset includes array‐genotype and phenotype data from 542 individuals (189 cases; 353 controls), imputed to the NHLBI TOPMedv5 haplotype reference panel. We used a generalized linear mixed‐model (SAIGE software) for the GWAS analysis. We analyzed two separate models; the first model accounted for sex, age, and population substructure, while the second model also included the dosage of APOEe4. In both models, we included a genetic relationship matrix as a random effect to account for any potential relatedness. To determine if the associations are specific to specific ancestries, we employed ancestry‐aware approaches using the RFMix software.
Result
APOE was significantly associated with AD with an effect size comparable to that found in non‐Hispanic white (NHW) populations (OR = 3.3(2.2‐4.8),pv = 8.0×10−10). Two additional known AD loci, TREML2 (pv = 0.008) and CLU (pv = 0.012), showed nominal significance Variants at three additional loci reached suggestive significance (pv |
| doi_str_mv | 10.1002/alz.077859 |
| format | Article |
| fullrecord | <record><control><sourceid>wiley_cross</sourceid><recordid>TN_cdi_crossref_primary_10_1002_alz_077859</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>ALZ077859</sourcerecordid><originalsourceid>FETCH-LOGICAL-c1139-d41a0accb5fc03ec50ad5b426e4e5c5cb941da13b567333f39b3e6d8afc975893</originalsourceid><addsrcrecordid>eNp9kL1OwzAUhS0EEqWw8AR3RgrYcZyfMar4kyrBAAtL5Ng3rSGJkW9LlU48As_IkxDUipHpHul-5wwfY-eCXwrO4yvdbi95luWqOGAToVQcqTgrDv9yyo_ZCdEr5wnPhZowKqHHDQRHb9B6sybwPZhl8J0n3yEIcAS0XiyQVmihHmCB_fj4_vzaOIugibxxeuXGGq3WdgDXwyOG9YfTPUHjA5TtdomuwwDWEWrCU3bU6JbwbH-n7Pnm-ml2F80fbu9n5TwyQsgisonQXBtTq8ZwiUZxbVWdxCkmqIwydZEIq4WsVZpJKRtZ1BJTm-vGFJnKCzllF7tdEzxRwKZ6D67TYagEr351VaOuaqdrhMUO3rgWh3_Iqpy_7Ds_QDhwOQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>A new risk locus on chromosome 1 is suggested by genome‐wide association study in Peruvians for Alzheimer disease</title><source>Wiley Online Library All Journals</source><creator>Akgun, Bilcag ; Cornejo‐Olivas, Mario ; Custodio, Nilton ; Rajabli, Farid ; Soto‐Añari, Marcio F. ; Montesinos, Rosa ; Yang, Zikun ; Huaman, Basilio C. ; Reyes‐Dumeyer, Dolly ; Cedeno, Jeffrey A ; Rivero, Joe ; Mena, Pedro R. ; Adams, Larry D. ; Whitehead, Patrice ; Hamilton‐Nelson, Kara L. ; Rios‐Pinto, Julia ; Medina‐Colque, Angel ; Dalgard, Clifton L. ; Isasi, Rosario ; Cornejo‐Herrera, Ivan ; Illanes‐Manrique, Maryenela ; Ochoa‐Valle, Edward ; Sarapura‐Castro, Elison ; Mejía, Koni K. ; Milla‐Neyra, Karina ; Castro‐Suarez, Sheila ; Martin, Eden R. ; Griswold, Anthony J. ; McInerney, Katalina ; Cuccaro, Michael L. ; Vance, Jeffery M. ; Beecham, Gary W. ; Pericak‐Vance, Margaret A. ; Tosto, Giuseppe</creator><creatorcontrib>Akgun, Bilcag ; Cornejo‐Olivas, Mario ; Custodio, Nilton ; Rajabli, Farid ; Soto‐Añari, Marcio F. ; Montesinos, Rosa ; Yang, Zikun ; Huaman, Basilio C. ; Reyes‐Dumeyer, Dolly ; Cedeno, Jeffrey A ; Rivero, Joe ; Mena, Pedro R. ; Adams, Larry D. ; Whitehead, Patrice ; Hamilton‐Nelson, Kara L. ; Rios‐Pinto, Julia ; Medina‐Colque, Angel ; Dalgard, Clifton L. ; Isasi, Rosario ; Cornejo‐Herrera, Ivan ; Illanes‐Manrique, Maryenela ; Ochoa‐Valle, Edward ; Sarapura‐Castro, Elison ; Mejía, Koni K. ; Milla‐Neyra, Karina ; Castro‐Suarez, Sheila ; Martin, Eden R. ; Griswold, Anthony J. ; McInerney, Katalina ; Cuccaro, Michael L. ; Vance, Jeffery M. ; Beecham, Gary W. ; Pericak‐Vance, Margaret A. ; Tosto, Giuseppe ; The Alzheimer’s Disease Sequencing Project (ADSP)</creatorcontrib><description>Background
Increasing ethnic/ancestral diversity in genetic studies is critical for defining the genetic architecture of Alzheimer disease (AD). Amerindian (AI) populations are substantially underrepresented in AD genetic studies. The Peruvian (PE) population, with up to ∼80% of AI ancestry, provides a unique opportunity to assess the role of AI ancestry in AD. We performed the first genome‐wide association study (GWAS) in the PE population to identify novel AD susceptibility loci and characterize known AD genetic risk loci.
Method
The PE dataset includes array‐genotype and phenotype data from 542 individuals (189 cases; 353 controls), imputed to the NHLBI TOPMedv5 haplotype reference panel. We used a generalized linear mixed‐model (SAIGE software) for the GWAS analysis. We analyzed two separate models; the first model accounted for sex, age, and population substructure, while the second model also included the dosage of APOEe4. In both models, we included a genetic relationship matrix as a random effect to account for any potential relatedness. To determine if the associations are specific to specific ancestries, we employed ancestry‐aware approaches using the RFMix software.
Result
APOE was significantly associated with AD with an effect size comparable to that found in non‐Hispanic white (NHW) populations (OR = 3.3(2.2‐4.8),pv = 8.0×10−10). Two additional known AD loci, TREML2 (pv = 0.008) and CLU (pv = 0.012), showed nominal significance Variants at three additional loci reached suggestive significance (pv<1×10−6): NFASC (pv = 9.4×10−8;chromosome 1), STK32A (pv = 9.3×10−7; chromosome 5), and LOC100132830 (pv = 6.7×10−7;chromosome 6). The NFASC locus neared genome‐wide significance in the APOE adjusted model (pv = 6.7×10−8). The haplotypes associated with AD at the NFASC locus were found to be of European origin. Additionally, the STK32A locus was found to have a protective effect specifically among individuals of AI background. We did not observe significant heterogeneity of effect at the APOE and LOC100132830 loci across different ancestral backgrounds.
Conclusion
PE GWAS identified a novel, promising AD susceptibility locus in the NFASC gene of European origin. We also detected a potential protective effect in the STK32A locus on AI background, emphasizing the importance of incorporating ancestry‐aware approaches in gene discovery in admixed populations.</description><identifier>ISSN: 1552-5260</identifier><identifier>EISSN: 1552-5279</identifier><identifier>DOI: 10.1002/alz.077859</identifier><language>eng</language><ispartof>Alzheimer's & dementia, 2023-12, Vol.19 (S12), p.n/a</ispartof><rights>2023 the Alzheimer's Association.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Falz.077859$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Falz.077859$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,777,781,1412,27905,27906,45555,45556</link.rule.ids></links><search><creatorcontrib>Akgun, Bilcag</creatorcontrib><creatorcontrib>Cornejo‐Olivas, Mario</creatorcontrib><creatorcontrib>Custodio, Nilton</creatorcontrib><creatorcontrib>Rajabli, Farid</creatorcontrib><creatorcontrib>Soto‐Añari, Marcio F.</creatorcontrib><creatorcontrib>Montesinos, Rosa</creatorcontrib><creatorcontrib>Yang, Zikun</creatorcontrib><creatorcontrib>Huaman, Basilio C.</creatorcontrib><creatorcontrib>Reyes‐Dumeyer, Dolly</creatorcontrib><creatorcontrib>Cedeno, Jeffrey A</creatorcontrib><creatorcontrib>Rivero, Joe</creatorcontrib><creatorcontrib>Mena, Pedro R.</creatorcontrib><creatorcontrib>Adams, Larry D.</creatorcontrib><creatorcontrib>Whitehead, Patrice</creatorcontrib><creatorcontrib>Hamilton‐Nelson, Kara L.</creatorcontrib><creatorcontrib>Rios‐Pinto, Julia</creatorcontrib><creatorcontrib>Medina‐Colque, Angel</creatorcontrib><creatorcontrib>Dalgard, Clifton L.</creatorcontrib><creatorcontrib>Isasi, Rosario</creatorcontrib><creatorcontrib>Cornejo‐Herrera, Ivan</creatorcontrib><creatorcontrib>Illanes‐Manrique, Maryenela</creatorcontrib><creatorcontrib>Ochoa‐Valle, Edward</creatorcontrib><creatorcontrib>Sarapura‐Castro, Elison</creatorcontrib><creatorcontrib>Mejía, Koni K.</creatorcontrib><creatorcontrib>Milla‐Neyra, Karina</creatorcontrib><creatorcontrib>Castro‐Suarez, Sheila</creatorcontrib><creatorcontrib>Martin, Eden R.</creatorcontrib><creatorcontrib>Griswold, Anthony J.</creatorcontrib><creatorcontrib>McInerney, Katalina</creatorcontrib><creatorcontrib>Cuccaro, Michael L.</creatorcontrib><creatorcontrib>Vance, Jeffery M.</creatorcontrib><creatorcontrib>Beecham, Gary W.</creatorcontrib><creatorcontrib>Pericak‐Vance, Margaret A.</creatorcontrib><creatorcontrib>Tosto, Giuseppe</creatorcontrib><creatorcontrib>The Alzheimer’s Disease Sequencing Project (ADSP)</creatorcontrib><title>A new risk locus on chromosome 1 is suggested by genome‐wide association study in Peruvians for Alzheimer disease</title><title>Alzheimer's & dementia</title><description>Background
Increasing ethnic/ancestral diversity in genetic studies is critical for defining the genetic architecture of Alzheimer disease (AD). Amerindian (AI) populations are substantially underrepresented in AD genetic studies. The Peruvian (PE) population, with up to ∼80% of AI ancestry, provides a unique opportunity to assess the role of AI ancestry in AD. We performed the first genome‐wide association study (GWAS) in the PE population to identify novel AD susceptibility loci and characterize known AD genetic risk loci.
Method
The PE dataset includes array‐genotype and phenotype data from 542 individuals (189 cases; 353 controls), imputed to the NHLBI TOPMedv5 haplotype reference panel. We used a generalized linear mixed‐model (SAIGE software) for the GWAS analysis. We analyzed two separate models; the first model accounted for sex, age, and population substructure, while the second model also included the dosage of APOEe4. In both models, we included a genetic relationship matrix as a random effect to account for any potential relatedness. To determine if the associations are specific to specific ancestries, we employed ancestry‐aware approaches using the RFMix software.
Result
APOE was significantly associated with AD with an effect size comparable to that found in non‐Hispanic white (NHW) populations (OR = 3.3(2.2‐4.8),pv = 8.0×10−10). Two additional known AD loci, TREML2 (pv = 0.008) and CLU (pv = 0.012), showed nominal significance Variants at three additional loci reached suggestive significance (pv<1×10−6): NFASC (pv = 9.4×10−8;chromosome 1), STK32A (pv = 9.3×10−7; chromosome 5), and LOC100132830 (pv = 6.7×10−7;chromosome 6). The NFASC locus neared genome‐wide significance in the APOE adjusted model (pv = 6.7×10−8). The haplotypes associated with AD at the NFASC locus were found to be of European origin. Additionally, the STK32A locus was found to have a protective effect specifically among individuals of AI background. We did not observe significant heterogeneity of effect at the APOE and LOC100132830 loci across different ancestral backgrounds.
Conclusion
PE GWAS identified a novel, promising AD susceptibility locus in the NFASC gene of European origin. We also detected a potential protective effect in the STK32A locus on AI background, emphasizing the importance of incorporating ancestry‐aware approaches in gene discovery in admixed populations.</description><issn>1552-5260</issn><issn>1552-5279</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNp9kL1OwzAUhS0EEqWw8AR3RgrYcZyfMar4kyrBAAtL5Ng3rSGJkW9LlU48As_IkxDUipHpHul-5wwfY-eCXwrO4yvdbi95luWqOGAToVQcqTgrDv9yyo_ZCdEr5wnPhZowKqHHDQRHb9B6sybwPZhl8J0n3yEIcAS0XiyQVmihHmCB_fj4_vzaOIugibxxeuXGGq3WdgDXwyOG9YfTPUHjA5TtdomuwwDWEWrCU3bU6JbwbH-n7Pnm-ml2F80fbu9n5TwyQsgisonQXBtTq8ZwiUZxbVWdxCkmqIwydZEIq4WsVZpJKRtZ1BJTm-vGFJnKCzllF7tdEzxRwKZ6D67TYagEr351VaOuaqdrhMUO3rgWh3_Iqpy_7Ds_QDhwOQ</recordid><startdate>202312</startdate><enddate>202312</enddate><creator>Akgun, Bilcag</creator><creator>Cornejo‐Olivas, Mario</creator><creator>Custodio, Nilton</creator><creator>Rajabli, Farid</creator><creator>Soto‐Añari, Marcio F.</creator><creator>Montesinos, Rosa</creator><creator>Yang, Zikun</creator><creator>Huaman, Basilio C.</creator><creator>Reyes‐Dumeyer, Dolly</creator><creator>Cedeno, Jeffrey A</creator><creator>Rivero, Joe</creator><creator>Mena, Pedro R.</creator><creator>Adams, Larry D.</creator><creator>Whitehead, Patrice</creator><creator>Hamilton‐Nelson, Kara L.</creator><creator>Rios‐Pinto, Julia</creator><creator>Medina‐Colque, Angel</creator><creator>Dalgard, Clifton L.</creator><creator>Isasi, Rosario</creator><creator>Cornejo‐Herrera, Ivan</creator><creator>Illanes‐Manrique, Maryenela</creator><creator>Ochoa‐Valle, Edward</creator><creator>Sarapura‐Castro, Elison</creator><creator>Mejía, Koni K.</creator><creator>Milla‐Neyra, Karina</creator><creator>Castro‐Suarez, Sheila</creator><creator>Martin, Eden R.</creator><creator>Griswold, Anthony J.</creator><creator>McInerney, Katalina</creator><creator>Cuccaro, Michael L.</creator><creator>Vance, Jeffery M.</creator><creator>Beecham, Gary W.</creator><creator>Pericak‐Vance, Margaret A.</creator><creator>Tosto, Giuseppe</creator><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>202312</creationdate><title>A new risk locus on chromosome 1 is suggested by genome‐wide association study in Peruvians for Alzheimer disease</title><author>Akgun, Bilcag ; Cornejo‐Olivas, Mario ; Custodio, Nilton ; Rajabli, Farid ; Soto‐Añari, Marcio F. ; Montesinos, Rosa ; Yang, Zikun ; Huaman, Basilio C. ; Reyes‐Dumeyer, Dolly ; Cedeno, Jeffrey A ; Rivero, Joe ; Mena, Pedro R. ; Adams, Larry D. ; Whitehead, Patrice ; Hamilton‐Nelson, Kara L. ; Rios‐Pinto, Julia ; Medina‐Colque, Angel ; Dalgard, Clifton L. ; Isasi, Rosario ; Cornejo‐Herrera, Ivan ; Illanes‐Manrique, Maryenela ; Ochoa‐Valle, Edward ; Sarapura‐Castro, Elison ; Mejía, Koni K. ; Milla‐Neyra, Karina ; Castro‐Suarez, Sheila ; Martin, Eden R. ; Griswold, Anthony J. ; McInerney, Katalina ; Cuccaro, Michael L. ; Vance, Jeffery M. ; Beecham, Gary W. ; Pericak‐Vance, Margaret A. ; Tosto, Giuseppe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1139-d41a0accb5fc03ec50ad5b426e4e5c5cb941da13b567333f39b3e6d8afc975893</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Akgun, Bilcag</creatorcontrib><creatorcontrib>Cornejo‐Olivas, Mario</creatorcontrib><creatorcontrib>Custodio, Nilton</creatorcontrib><creatorcontrib>Rajabli, Farid</creatorcontrib><creatorcontrib>Soto‐Añari, Marcio F.</creatorcontrib><creatorcontrib>Montesinos, Rosa</creatorcontrib><creatorcontrib>Yang, Zikun</creatorcontrib><creatorcontrib>Huaman, Basilio C.</creatorcontrib><creatorcontrib>Reyes‐Dumeyer, Dolly</creatorcontrib><creatorcontrib>Cedeno, Jeffrey A</creatorcontrib><creatorcontrib>Rivero, Joe</creatorcontrib><creatorcontrib>Mena, Pedro R.</creatorcontrib><creatorcontrib>Adams, Larry D.</creatorcontrib><creatorcontrib>Whitehead, Patrice</creatorcontrib><creatorcontrib>Hamilton‐Nelson, Kara L.</creatorcontrib><creatorcontrib>Rios‐Pinto, Julia</creatorcontrib><creatorcontrib>Medina‐Colque, Angel</creatorcontrib><creatorcontrib>Dalgard, Clifton L.</creatorcontrib><creatorcontrib>Isasi, Rosario</creatorcontrib><creatorcontrib>Cornejo‐Herrera, Ivan</creatorcontrib><creatorcontrib>Illanes‐Manrique, Maryenela</creatorcontrib><creatorcontrib>Ochoa‐Valle, Edward</creatorcontrib><creatorcontrib>Sarapura‐Castro, Elison</creatorcontrib><creatorcontrib>Mejía, Koni K.</creatorcontrib><creatorcontrib>Milla‐Neyra, Karina</creatorcontrib><creatorcontrib>Castro‐Suarez, Sheila</creatorcontrib><creatorcontrib>Martin, Eden R.</creatorcontrib><creatorcontrib>Griswold, Anthony J.</creatorcontrib><creatorcontrib>McInerney, Katalina</creatorcontrib><creatorcontrib>Cuccaro, Michael L.</creatorcontrib><creatorcontrib>Vance, Jeffery M.</creatorcontrib><creatorcontrib>Beecham, Gary W.</creatorcontrib><creatorcontrib>Pericak‐Vance, Margaret A.</creatorcontrib><creatorcontrib>Tosto, Giuseppe</creatorcontrib><creatorcontrib>The Alzheimer’s Disease Sequencing Project (ADSP)</creatorcontrib><collection>CrossRef</collection><jtitle>Alzheimer's & dementia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Akgun, Bilcag</au><au>Cornejo‐Olivas, Mario</au><au>Custodio, Nilton</au><au>Rajabli, Farid</au><au>Soto‐Añari, Marcio F.</au><au>Montesinos, Rosa</au><au>Yang, Zikun</au><au>Huaman, Basilio C.</au><au>Reyes‐Dumeyer, Dolly</au><au>Cedeno, Jeffrey A</au><au>Rivero, Joe</au><au>Mena, Pedro R.</au><au>Adams, Larry D.</au><au>Whitehead, Patrice</au><au>Hamilton‐Nelson, Kara L.</au><au>Rios‐Pinto, Julia</au><au>Medina‐Colque, Angel</au><au>Dalgard, Clifton L.</au><au>Isasi, Rosario</au><au>Cornejo‐Herrera, Ivan</au><au>Illanes‐Manrique, Maryenela</au><au>Ochoa‐Valle, Edward</au><au>Sarapura‐Castro, Elison</au><au>Mejía, Koni K.</au><au>Milla‐Neyra, Karina</au><au>Castro‐Suarez, Sheila</au><au>Martin, Eden R.</au><au>Griswold, Anthony J.</au><au>McInerney, Katalina</au><au>Cuccaro, Michael L.</au><au>Vance, Jeffery M.</au><au>Beecham, Gary W.</au><au>Pericak‐Vance, Margaret A.</au><au>Tosto, Giuseppe</au><aucorp>The Alzheimer’s Disease Sequencing Project (ADSP)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A new risk locus on chromosome 1 is suggested by genome‐wide association study in Peruvians for Alzheimer disease</atitle><jtitle>Alzheimer's & dementia</jtitle><date>2023-12</date><risdate>2023</risdate><volume>19</volume><issue>S12</issue><epage>n/a</epage><issn>1552-5260</issn><eissn>1552-5279</eissn><abstract>Background
Increasing ethnic/ancestral diversity in genetic studies is critical for defining the genetic architecture of Alzheimer disease (AD). Amerindian (AI) populations are substantially underrepresented in AD genetic studies. The Peruvian (PE) population, with up to ∼80% of AI ancestry, provides a unique opportunity to assess the role of AI ancestry in AD. We performed the first genome‐wide association study (GWAS) in the PE population to identify novel AD susceptibility loci and characterize known AD genetic risk loci.
Method
The PE dataset includes array‐genotype and phenotype data from 542 individuals (189 cases; 353 controls), imputed to the NHLBI TOPMedv5 haplotype reference panel. We used a generalized linear mixed‐model (SAIGE software) for the GWAS analysis. We analyzed two separate models; the first model accounted for sex, age, and population substructure, while the second model also included the dosage of APOEe4. In both models, we included a genetic relationship matrix as a random effect to account for any potential relatedness. To determine if the associations are specific to specific ancestries, we employed ancestry‐aware approaches using the RFMix software.
Result
APOE was significantly associated with AD with an effect size comparable to that found in non‐Hispanic white (NHW) populations (OR = 3.3(2.2‐4.8),pv = 8.0×10−10). Two additional known AD loci, TREML2 (pv = 0.008) and CLU (pv = 0.012), showed nominal significance Variants at three additional loci reached suggestive significance (pv<1×10−6): NFASC (pv = 9.4×10−8;chromosome 1), STK32A (pv = 9.3×10−7; chromosome 5), and LOC100132830 (pv = 6.7×10−7;chromosome 6). The NFASC locus neared genome‐wide significance in the APOE adjusted model (pv = 6.7×10−8). The haplotypes associated with AD at the NFASC locus were found to be of European origin. Additionally, the STK32A locus was found to have a protective effect specifically among individuals of AI background. We did not observe significant heterogeneity of effect at the APOE and LOC100132830 loci across different ancestral backgrounds.
Conclusion
PE GWAS identified a novel, promising AD susceptibility locus in the NFASC gene of European origin. We also detected a potential protective effect in the STK32A locus on AI background, emphasizing the importance of incorporating ancestry‐aware approaches in gene discovery in admixed populations.</abstract><doi>10.1002/alz.077859</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| title | A new risk locus on chromosome 1 is suggested by genome‐wide association study in Peruvians for Alzheimer disease |
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