African Ancestry GWAS of Dementia in a Large Military Cohort Identifies Significant Risk Loci

Sherva, Richard; Zhang, Rui; Sahelijo, Nathan; Jun, Gyungah; Anglin-Foote, Tori; Chanfreau, Catherine; Cho, Kelly; Fonda, Jennifer R.; Gaziano, J. Michael; Harrington, Kelly; Ho, Yuk‐Lam; Kremen, William S.; Litkowski, Elizabeth; Lynch, Julie; Neale, Zoë; Roussos, Panos; Marra, David E; Mez, Jesse; Salat, David H.; Tsuang, Debby W.; Wolf, Erika J.; Zeng, Qing; Panizzon, Matthew S.; Merritt, Victoria C.; Farrer, Lindsay A.; Hauger, Richard L.; Logue, Mark W.

doi:10.1101/2022.05.25.22275553

Cited by 5 publications

(5 citation statements)

References 60 publications

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“…The most extensive African American GWAS to date, drawing from a military cohort of around 22,000 individuals and a proxy GWAS involving approximately 50,000 individuals, identified significant associations with established AD risk genes such as TREM2 , CD2AP , and ABCA7 . Notably, distinct lead variants were observed in these loci compared to those found in European cohorts 12 .…”

Section: Resultsmentioning

confidence: 81%

“…While the inclusion of diverse populations in genetic research for AD is arguably better than what is seen for some of the atypical dementias, the largest study size for a non-European population 12 was still only 7% of the total sample size for the largest European AD GWAS. The largest meta-GWAS of PD risk in individuals of European ancestry found 90 significant risk signals across 78 genomic regions.…”

Section: Alzheimer's Diseasementioning

confidence: 99%

“…Largest European GWAS: Ferrari 2014 Total samples: 12,928 There are no multi-ancestry or non-European studies in FTD.…”

Section: Frontotemporal Dementiamentioning

confidence: 99%

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Assessing the lack of diversity in genetics research across neurodegenerative diseases: a systematic review of the GWAS Catalog and literature

Jonson,

Levine,

Lake

et al. 2024

Preprint

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Importance:The under-representation of participants with non-European ancestry in genome-wide association studies (GWAS) is a critical issue that has significant implications, including hindering the progress of precision medicine initiatives. This issue is particularly significant in the context of neurodegenerative diseases (NDDs), where current therapeutic approaches have shown limited success. Addressing this under-representation is crucial to harnessing the full potential of genomic medicine in underserved communities and improving outcomes for NDD patients.ObjectiveOur primary objective was to assess the representation of non-European ancestry participants in genetic discovery efforts related to NDDs. We aimed to quantify the extent of inclusion of diverse ancestry groups in NDD studies and determine the number of associated loci identified in more inclusive studies. Specifically, we sought to highlight the disparities in research efforts and outcomes between studies predominantly involving European ancestry participants and those deliberately targeting non-European or multi-ancestry populations across NDDs.Evidence Review:We conducted a systematic review utilizing existing GWAS results and publications to assess the inclusion of diverse ancestry groups in neurodegeneration and neurogenetics studies. Our search encompassed studies published up to the end of 2022, with a focus on identifying research that deliberately included non-European or multi-ancestry cohorts. We employed rigorous methods for the inclusion of identified articles and quality assessment.FindingsOur review identified a total of 123 NDD GWAS. Strikingly, 82% of these studies predominantly featured participants of European ancestry. Endeavors specifically targeting non-European or multi-ancestry populations across NDDs identified only 52 risk loci. This contrasts with predominantly European studies, which reported over 90 risk loci for a single disease.Encouragingly, over 65% of these discoveries occurred in 2020 or later, indicating a recent increase in studies deliberately including non-European cohorts.Conclusions and relevanceOur findings underscore the pressing need for increased diversity in neurodegenerative research. The significant under-representation of non-European ancestry participants in NDD GWAS limits our understanding of the genetic underpinnings of these diseases. To advance the field of neurodegenerative research and develop more effective therapies, it is imperative that future investigations prioritize and harness the genomic diversity present within and across global populations.Abstract and highlightsKey PointsQuestionWhat is the state of ancestral inclusivity in genetic studies of neurodegenerative diseases?FindingsA systematic review of 123 publications on neurodegenerative diseases shows a focus on European populations, with only 18% of studies including any non-European ancestry data. Among 52 novel loci identified in non-European studies, 28 were from multi-ancestry studies (which included Europeans), 21 from East Asian studies, and 3 from other populations.MeaningThis significant disparity underscores the need for more inclusive research approaches in neurodegenerative diseases, emphasizing multi-ancestry and non-European populations to advance precision medicine and develop treatments effective for diverse populations.

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Section: Resultsmentioning

confidence: 81%

Section: Alzheimer's Diseasementioning

confidence: 99%

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Assessing the lack of diversity in genetics research across neurodegenerative diseases: a systematic review of the GWAS Catalog and literature

Jonson,

Levine,

Lake

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…In African populations, the genetic association of the ε4 allele with AD risk is weak or sometimes absent, but relatively present in African American individuals (ε4/ε4 OR: 5.7) (Farrer et al, 1997). The most recent and largest genomewide association meta-analysis of African American individuals also confirmed APOE as the strongest risk factor of AD in this group (Sherva et al, 2022). This may be attributable to the presence of European admixture in African Americans, thus accounting for the population differences in the effect of the ε4 allele.…”

Section: Apoementioning

confidence: 87%

“…Several large GWAS have been conducted in non-European ancestry populations for AD, including the largest African-American AD GWAS to date, which utilized data derived from the Million Veterans Program ( Sherva et al, 2022 ), as well as a recent publication from the ADGC ( Kunkle et al, 2021 ). Large-scale studies have also been conducted in East Asian populations from China and Japan ( Jia et al, 2021 ; Shigemizu et al, 2021 ).…”

Section: Genetic Contribution To Neurodegenerative Disease In Non-eur...mentioning

confidence: 99%

The influence of 17q21.31 and APOE genetic ancestry on neurodegenerative disease risk

Harerimana

Goate

Bowles

2022

Front. Aging Neurosci.

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Advances in genomic research over the last two decades have greatly enhanced our knowledge concerning the genetic landscape and pathophysiological processes involved in multiple neurodegenerative diseases. However, current insights arise almost exclusively from studies on individuals of European ancestry. Despite this, studies have revealed that genetic variation differentially impacts risk for, and clinical presentation of neurodegenerative disease in non-European populations, conveying the importance of ancestry in predicting disease risk and understanding the biological mechanisms contributing to neurodegeneration. We review the genetic influence of two important disease-associated loci, 17q21.31 (the “MAPT locus”) and APOE, to neurodegenerative disease risk in non-European populations, touching on global population differences and evolutionary genetics by ancestry that may underlie some of these differences. We conclude there is a need to increase representation of non-European ancestry individuals in genome-wide association studies (GWAS) and biomarker analyses in order to help resolve existing disparities in understanding risk for, diagnosis of, and treatment for neurodegenerative diseases in diverse populations.

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Assessing the lack of diversity in genetics research across neurodegenerative diseases: A systematic review of the GWAS Catalog and literature

Jonson,

Levine,

Lake

et al. 2024

Alzheimer's & Dementia

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The under‐representation of non‐European cohorts in neurodegenerative disease genome‐wide association studies (GWAS) hampers precision medicine efforts. Despite the inherent genetic and phenotypic diversity in these diseases, GWAS research consistently exhibits a disproportionate emphasis on participants of European ancestry. This study reviews GWAS up to 2022, focusing on non‐European or multi‐ancestry neurodegeneration studies. We conducted a systematic review of GWAS results and publications up to 2022, focusing on non‐European or multi‐ancestry neurodegeneration studies. Rigorous article inclusion and quality assessment methods were employed. Of 123 neurodegenerative disease (NDD) GWAS reviewed, 82% predominantly featured European ancestry participants. A single European study identified over 90 risk loci, compared to a total of 50 novel loci in identified in all non‐European or multi‐ancestry studies. Notably, only six of the loci have been replicated. The significant under‐representation of non‐European ancestries in NDD GWAS hinders comprehensive genetic understanding. Prioritizing genomic diversity in future research is crucial for advancing NDD therapies and understanding.Highlights Eighty‐two percent of neurodegenerative genome‐wide association studies (GWAS) focus on Europeans. Only 6 of 50 novel neurodegenerative disease (NDD) genetic loci have been replicated. Lack of diversity significantly hampers understanding of NDDs. Increasing diversity in NDD genetic research is urgently required. New initiatives are aiming to enhance diversity in NDD research.

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African Ancestry GWAS of Dementia in a Large Military Cohort Identifies Significant Risk Loci

Cited by 5 publications

References 60 publications

Assessing the lack of diversity in genetics research across neurodegenerative diseases: a systematic review of the GWAS Catalog and literature

Assessing the lack of diversity in genetics research across neurodegenerative diseases: a systematic review of the GWAS Catalog and literature

The influence of 17q21.31 and APOE genetic ancestry on neurodegenerative disease risk

Assessing the lack of diversity in genetics research across neurodegenerative diseases: A systematic review of the GWAS Catalog and literature

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