Two rare <i>AKAP9</i> variants are associated with Alzheimer's disease in African Americans

Logue, Mark W.; Schu, Matthew; Vardarajan, Badri N.; Farrell, John; Bennett, David A.; Buxbaum, Joseph D.; Byrd, Goldie S.; Ertekin-Taner, Nilüfer; Evans, Denis A.; Foroud, Tatiana; Goate, Alison M.; Graff‐Radford, Neill R.; Kamboh, M. Ilyas; Kukull, Walter A.; Manly, Jennifer J.; Haines, Jonathan L.; Mayeux, Richard; Pericak‐Vance, Margaret A.; Schellenberg, Gerard D.; Lunetta, Kathryn L.; Baldwin, Clinton T.; Fallin, M. Daniele; Farrer, Lindsay A.

doi:10.1016/j.jalz.2014.06.010

Cited by 95 publications

(91 citation statements)

References 71 publications

(48 reference statements)

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“…p.R434W was predicted to be damaging by SIFT and Polyphen and had a highly deleterious CADD score of 32. Previously implicated variants in AKAP9 40 (rs144662445 and rs149979685) were each observed in one LOAD patient.…”

Section: Resultsmentioning

confidence: 88%

“…A variant in AKAP9, (p.R434W), a gene previously associated with LOAD in a case–control study among African Americans,40 segregated in two large families and was nominally associated with LOAD, with fivefold increased risk adjusted for age, sex, and APOE‐ε4 . The two different variants in AKAP9 were previously identified, were considered rare in populations African‐descent, and were not present in European‐descent or East Asian‐descent individuals in the 1000 Genomes database.…”

Section: Discussionmentioning

confidence: 99%

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Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

Vardarajan

Barral

Jaworski

et al. 2018

Ann Clin Transl Neurol

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ObjectiveTo identify rare causal variants underlying known loci that segregate with late‐onset Alzheimer's disease (LOAD) in multiplex families.MethodsWe analyzed whole genome sequences (WGS) from 351 members of 67 Caribbean Hispanic (CH) families from Dominican Republic and New York multiply affected by LOAD. Members of 67 CH and additional 47 Caucasian families underwent WGS as a part of the Alzheimer's Disease Sequencing Project (ADSP). All members of 67 CH families, an additional 48 CH families and an independent CH case‐control cohort were subsequently genotyped for validation. Patients met criteria for LOAD, and controls were determined to be dementia free. We investigated rare variants segregating within families and gene‐based associations with disease within LOAD GWAS loci.ResultsA variant in AKAP9, p.R434W, segregated significantly with LOAD in two large families (OR = 5.77, 95% CI: 1.07–30.9, P = 0.041). In addition, missense mutations in MYRF and ASRGL1 under previously reported linkage peaks at 7q14.3 and 11q12.3 segregated completely in one family and in follow‐up genotyping both were nominally significant (P < 0.05). We also identified rare variants in a number of genes associated with LOAD in prior genome wide association studies, including CR1 (P = 0.049), BIN1 (P = 0.0098) and SLC24A4 (P = 0.040).Conclusions and RelevanceRare variants in multiple genes influence the risk of LOAD disease in multiplex families. These results suggest that rare variants may underlie loci identified in genome wide association studies.

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Section: Resultsmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

Vardarajan

Barral

Jaworski

et al. 2018

Ann Clin Transl Neurol

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“…The substitution results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro, by reducing the β-cleavage of APP. Additional variations at a number of loci, including UNC5C [31,32] , ADAM10 [33], ZNF628 [34] and AKAP9 (in an African American AD cohort) [35], show promise and require independent replication. Since sample size requirements increase with both decreasing minor allele frequency and decreasing effect size, NGS studies are underpowered to identify rare variants with the effect sizes expected in complex disease.…”

Section: Genetic Findingsmentioning

confidence: 99%

Defining the Genetic Architecture of Alzheimer's Disease: Where Next?

Sims

Williams²

2015

Neurodegener Dis

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Background: Late-onset Alzheimer's disease is a genetically complex disorder. For 17 years, APOE was the only known susceptibility gene for disease. Through mostly genome-wide association studies, 25 loci are now known to associate with late-onset Alzheimer's disease. These susceptibility loci are not randomly distributed with respect to their functions. In fact, pathway analysis implicates significant enrichment of immunity, endocytosis, cholesterol metabolism, and ubiquitination in disease. Summary: Twenty-five loci have now been reliably shown to associate with Alzheimer's disease. However, a significant proportion of genetic variation in disease pathology is yet to be detected. Rare variation is being investigated through exome chip and next-generation sequencing experiments, which have already identified new protective and risk variants. Using a polygenic risk score approach, it is now possible to identify population groups with the greatest and fewest biological susceptibilities to disease. This method has proved more effective in predicting disease status than individual, genome-wide significant variants of small/moderate effect. Future studies will establish the specific functional changes that contribute to disease by piloting novel cellular modelling techniques using reprogrammed induced pluripotent stem cells from individuals with selected risk profiles. This will allow a variety of models to be produced to help understand disease mechanisms and test new drug therapies. Key Messages: Alzheimer's disease is a polygenic trait that has been linked to deficits in immunity, endocytosis, cholesterol metabolism and ubiquitination. Future work will focus on identifying rare disease susceptibility loci, unpicking the functional significance of the known risk loci and piloting novel cellular modelling techniques.

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“…Next-generation sequencing has also enabled the identification of rare variants, one of the most consistent being the R47H variant in the TREM2 gene locus (Guerreiro et al, 2013; Jonsson et al, 2013) which affect the risk of AD previously not identified in GWAS (Giri et al, 2016; Lambert et al, 2013; Naj and Schellenberg, 2016). Although most studies utilize Caucasian populations, further risk variants have been identified through next-generation sequencing in African-American individuals within the gene AKAP9 (Giri et al, 2016; Logue et al, 2014). Conversely, protective variants have also been identified including a small coding deletion (rs10553596) within the CASP7 gene associated with reduced incidence of AD among individuals with the APOE ε4ε4 genotype in 4 independent imputed data sets (Ayers et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease

Chaudhury

Patel

Barber

et al. 2018

Neurobiology of Aging

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Sporadic early-onset Alzheimer’s disease (sEOAD) exhibits the symptoms of late-onset Alzheimer’s disease but lacks the familial aspect of the early-onset familial form. The genetics of Alzheimer’s disease (AD) identifies APOE ε4 to be the greatest risk factor; however, it is a complex disease involving both environmental risk factors and multiple genetic loci. Polygenic risk scores (PRSs) accumulate the total risk of a phenotype in an individual based on variants present in their genome. We determined whether sEOAD cases had a higher PRS compared to controls. A cohort of sEOAD cases was genotyped on the NeuroX array, and PRSs were generated using PRSice. The target data set consisted of 408 sEOAD cases and 436 controls. The base data set was collated by the International Genomics of Alzheimer’s Project consortium, with association data from 17,008 late-onset Alzheimer’s disease cases and 37,154 controls, which can be used for identifying sEOAD cases due to having shared phenotype. PRSs were generated using all common single nucleotide polymorphisms between the base and target data set, PRS were also generated using only single nucleotide polymorphisms within a 500 kb region surrounding the APOE gene. Sex and number of APOE ε2 or ε4 alleles were used as variables for logistic regression and combined with PRS. The results show that PRS is higher on average in sEOAD cases than controls, although there is still overlap among the whole cohort. Predictive ability of identifying cases and controls using PRSice was calculated with 72.9% accuracy, greater than the APOE locus alone (65.2%). Predictive ability was further improved with logistic regression, identifying cases and controls with 75.5% accuracy.

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Two rare AKAP9 variants are associated with Alzheimer's disease in African Americans

Cited by 95 publications

References 71 publications

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

Defining the Genetic Architecture of Alzheimer's Disease: Where Next?

Polygenic risk score in postmortem diagnosed sporadic early-onset Alzheimer's disease

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