Genome-Wide Association Study of Incident Dementia in a Community-Based Sample of Older Subjects

Overview

Journal J Alzheimers Dis

Publisher Sage Publications

Specialties Geriatrics
Neurology

Date 2022 Jun 13

PMID 35694926

Authors

Jordan D Harper

Kang-Hsien Fan

M Muaaz Aslam

Beth E Snitz

Steven T DeKosky

Oscar L Lopez

Eleanor Feingold

M Ilyas Kamboh

Affiliations

Soon will be listed here.

Abstract

Background: Alzheimer's disease (AD) is a complex disease influenced by the environment and genetics; however, much of the genetic component remains unaccounted for.

Objective: The purpose of this work was to use genome-wide association analyses to detect genetic associations with incident AD in a sample of older adults aged 75 and above.

Methods: We performed a genome-wide association study (GWAS) on genome-wide genotyped and imputed data (14,072,053 variants) on the Gingko Evaluation of Memory (GEM) study sample consisting of 424 incident dementia (mean age = 84.46±3.91) and 2,206 non-demented (mean age = 84.55±3.23) subjects.

Results: The established association of APOE*4 carriers with AD was confirmed in this community-based sample of older subjects (odds ratio (OR) = 2.22; p = 9.36E-14) and was stronger in females (OR = 2.72; p = 1.74E-10) than in males (OR = 1.88; p = 2.43E-05). We observed a novel genome-wide significant (GWS) locus on chromosome 12 near ncRNA LOC105369711/rs148377161 (OR = 3.31; p = 1.66E-08). In addition, sex-stratified analyses identified two novel associations in males: one near ncRNA LOC729987/rs140076909 on chromosome 1 (OR = 4.51; p = 3.72E-08) and the other approaching GWS near ncRNA LOC105375138/rs117803234 on chromosome 7 (OR = 3.76; p = 6.93E-08).

Conclusion: The use of community-based samples of older individuals and incident dementia as a phenotype may be a helpful approach for the identification of novel genes for AD, which may not be detected in standard case-control studies. Replication of these signals and further studies of these regions and genes will help to provide a clearer picture for their role in AD.

Citing Articles

Sex-stratified genome-wide meta-analysis identifies novel loci for cognitive decline in older adults.

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Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer's disease risk.

Aslam M, Fan K, Lawrence E, Bedison M, Snitz B, DeKosky S Mol Psychiatry. 2023; 28(10):4451-4462.

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References

Ganguli M, Chandra V, Kamboh M, Johnston J, Dodge H, Thelma B . Apolipoprotein E polymorphism and Alzheimer disease: The Indo-US Cross-National Dementia Study. Arch Neurol. 2000; 57(6):824-30. DOI: 10.1001/archneur.57.6.824. View

Farrer L, Cupples L, Haines J, Hyman B, Kukull W, Mayeux R . Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997; 278(16):1349-56. View

Kuo M, Liu S, Hsu Y, Wu R . The role of noncoding RNAs in Parkinson's disease: biomarkers and associations with pathogenic pathways. J Biomed Sci. 2021; 28(1):78. PMC: 8603508. DOI: 10.1186/s12929-021-00775-x. View

Ridge P, Hoyt K, Boehme K, Mukherjee S, Crane P, Haines J . Assessment of the genetic variance of late-onset Alzheimer's disease. Neurobiol Aging. 2016; 41:200.e13-200.e20. PMC: 4948179. DOI: 10.1016/j.neurobiolaging.2016.02.024. View

Kamboh M . Genomics and Functional Genomics of Alzheimer's Disease. Neurotherapeutics. 2021; 19(1):152-172. PMC: 9130391. DOI: 10.1007/s13311-021-01152-0. View

. 2021 Alzheimer's disease facts and figures. Alzheimers Dement. 2021; 17(3):327-406. DOI: 10.1002/alz.12328. View

Snitz B, OMeara E, Carlson M, Arnold A, Ives D, Rapp S . Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial. JAMA. 2009; 302(24):2663-70. PMC: 2832285. DOI: 10.1001/jama.2009.1913. View

Genin E, Hannequin D, Wallon D, Sleegers K, Hiltunen M, Combarros O . APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry. 2011; 16(9):903-7. PMC: 3162068. DOI: 10.1038/mp.2011.52. View

Pruim R, Welch R, Sanna S, Teslovich T, Chines P, Gliedt T . LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010; 26(18):2336-7. PMC: 2935401. DOI: 10.1093/bioinformatics/btq419. View

10.

Teng E, Chui H . The Modified Mini-Mental State (3MS) examination. J Clin Psychiatry. 1987; 48(8):314-8. View

11.

Gatz M, Reynolds C, Fratiglioni L, Johansson B, Mortimer J, Berg S . Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006; 63(2):168-74. DOI: 10.1001/archpsyc.63.2.168. View

12.

Barry G . Integrating the roles of long and small non-coding RNA in brain function and disease. Mol Psychiatry. 2014; 19(4):410-6. DOI: 10.1038/mp.2013.196. View

13.

DeKosky S, Fitzpatrick A, Ives D, Saxton J, Williamson J, Lopez O . The Ginkgo Evaluation of Memory (GEM) study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia. Contemp Clin Trials. 2006; 27(3):238-53. DOI: 10.1016/j.cct.2006.02.007. View

14.

DeKosky S, Williamson J, Fitzpatrick A, Kronmal R, Ives D, Saxton J . Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA. 2008; 300(19):2253-62. PMC: 2823569. DOI: 10.1001/jama.2008.683. View

15.

Wingo T, Lah J, Levey A, Cutler D . Autosomal recessive causes likely in early-onset Alzheimer disease. Arch Neurol. 2011; 69(1):59-64. PMC: 3332307. DOI: 10.1001/archneurol.2011.221. View

16.

Wang H, Lo M, Rosenthal S, Makowski C, Andreassen O, Salem R . Similar Genetic Architecture of Alzheimer's Disease and Differential Effect Between Sexes. Front Aging Neurosci. 2021; 13:674318. PMC: 8194397. DOI: 10.3389/fnagi.2021.674318. View

17.

Kunkle B, Grenier-Boley B, Sims R, Bis J, Damotte V, Naj A . Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 2019; 51(3):414-430. PMC: 6463297. DOI: 10.1038/s41588-019-0358-2. View

18.

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira M, Bender D . PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007; 81(3):559-75. PMC: 1950838. DOI: 10.1086/519795. View

19.

Wu Y, Kuo H . Functional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases. J Biomed Sci. 2020; 27(1):49. PMC: 7140545. DOI: 10.1186/s12929-020-00636-z. View

20.

Nguyen L, Chau R, Krichevsky A . Small Molecule Drugs Targeting Non-Coding RNAs as Treatments for Alzheimer's Disease and Related Dementias. Genes (Basel). 2021; 12(12). PMC: 8701955. DOI: 10.3390/genes12122005. View