AD GWAS in African Americans Confirms, Reshuffles AlzGene List

African Americans carrying a variant in a cholesterol-processing gene have double the risk for Alzheimer’s than non-carriers. This gene, for a membrane transporter protein called ABCA7, is the greatest difference between African American and Caucasian Alzheimer’s risk to emerge from the largest genomewide association study (GWAS) for AD performed in African Americans to date. The study appears April 10 in the Journal of the American Medical Association. In African Americans, ABCA7 variation is the strongest genetic risk factor for AD outside of the ApoE4 allele. Other than that, the genes involved in African American AD risk paralleled those in whites, reported the study authors representing the Alzheimer's Disease Genetics Consortium.

Led by senior author Richard Mayeux at Columbia University in New York City, the researchers examined single-nucleotide polymorphisms from nearly 2,000 people with late-onset Alzheimer’s, and almost 4,000 control participants. The group collected all the data it could get from African Americans seen at more than 20 study centers, said first author Christiane Reitz, also at Columbia.

While many of the previously reported GWAS data come from people of European and European American ancestry, Reitz noted that it is important to investigate whether those genetic findings extend to people beyond that white slice of humanity. A GWAS in Hispanics is ongoing.

Several of the genes the current study picked out in African Americans matched those found in GWAS with white people. ApoE4 was the strongest risk factor; a single copy more than doubled risk of Alzheimer’s with an odds ratio of 2.31 in this report. “Replicating an association for the same alleles in different ethnic groups strengthens the case for these variants being important in increasing disease susceptibility,” commented Robert Nussbaum of the University of California, San Francisco, in an editorial accompanying the publication.

After ApoE, ABCA7 was second on the hit list. ABCA7 variants had been reported to increase risk in white people, but ABCA7 was in the middle of the pack among genes linked to AD, most of which boost risk by an average of 10-20 percent, Reitz said (Hollingworth et al., 2011). ABCA7 currently ranks fourth on the AlzGene Top 10. In the new study’s African American population, an ABCA7 variant increased one’s chances of AD by almost double, with an odds ratio of 1.79.

This kind of race-based difference is not uncommon, Reitz noted. She suspects that the ABCA7 polymorphisms found in Caucasians point to specific functional mutations different from those carried by African Americans, but the researchers have not yet sequenced the gene to check. It is also possible that the genetic background of each race, as well as environmental factors, conspire with ABCA7 variants to produce a higher risk in African American carriers than in whites.

It is too early to think about genetic testing or ABCA7-based therapies, Reitz said. For now, researchers have to confirm the disease association in an independent population and study the biological function of the gene. That is no small task. ABCA7’s functions fit with the AD literature in that lipid dysregulation and cardiovascular disease are known risk factors (Breteler, 2000; Shepardson et al., 2011). ABCA7 encodes an ATP-binding transporter that participates in lipoprotein biogenesis, and secretion of phospholipids and cholesterol (Tanaka et al., 2011). It also influences the transport of amyloid precursor protein across the plasma membrane (Chan et al., 2008). “There are multiple ways in which ABCA might affect risk of late-onset Alzheimer's disease,” the study authors wrote.—Amber Dance

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Jones N, Stretton A, Thomas C, Richards A, Ivanov D, Widdowson C, Chapman J, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Beaumont H, Warden D, Wilcock G, Love S, Kehoe PG, Hooper NM, Vardy ER, Hardy J, Mead S, Fox NC, Rossor M, Collinge J, Maier W, Jessen F, Rüther E, Schürmann B, Heun R, Kölsch H, van den Bussche H, Heuser I, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Gallacher J, Hüll M, Rujescu D, Giegling I, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Sleegers K, Bettens K, Engelborghs S, De Deyn PP, Van Broeckhoven C, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Tsolaki M, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Pankratz VS, Sando SB, Aasly JO, Barcikowska M, Wszolek ZK, Dickson DW, Graff-Radford NR, Petersen RC, , van Duijn CM, Breteler MM, Ikram MA, DeStefano AL, Fitzpatrick AL, Lopez O, Launer LJ, Seshadri S, Berr C, Campion D, Epelbaum J, Dartigues JF, Tzourio C, Alpérovitch A, Lathrop M, Feulner TM, Friedrich P, Riehle C, Krawczak M, Schreiber S, Mayhaus M, Nicolhaus S, Wagenpfeil S, Steinberg S, Stefansson H, Stefansson K, Snædal J, Björnsson S, Jonsson PV, Chouraki V, Genier-Boley B, Hiltunen M, Soininen H, Combarros O, Zelenika D, Delepine M, Bullido MJ, Pasquier F, Mateo I, Frank-Garcia A, Porcellini E, Hanon O, Coto E, Alvarez V, Bosco P, Siciliano G, Mancuso M, Panza F, Solfrizzi V, Nacmias B, Sorbi S, Bossù P, Piccardi P, Arosio B, Annoni G, Seripa D, Pilotto A, Scarpini E, Galimberti D, Brice A, Hannequin D, Licastro F, Jones L, Holmans PA, Jonsson T, Riemenschneider M, Morgan K, Younkin SG, Owen MJ, O'Donovan M, Amouyel P, Williams J. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet. 2011 May;43(5):429-35. PubMed.
  2. Breteler MM. Vascular risk factors for Alzheimer's disease: an epidemiologic perspective. Neurobiol Aging. 2000 Mar-Apr;21(2):153-60. PubMed.
  3. Shepardson NE, Shankar GM, Selkoe DJ. Cholesterol level and statin use in Alzheimer disease: I. Review of epidemiological and preclinical studies. Arch Neurol. 2011 Oct;68(10):1239-44. PubMed.
  4. Tanaka N, Abe-Dohmae S, Iwamoto N, Yokoyama S. Roles of ATP-binding cassette transporter A7 in cholesterol homeostasis and host defense system. J Atheroscler Thromb. 2011;18(4):274-81. PubMed.
  5. Chan SL, Kim WS, Kwok JB, Hill AF, Cappai R, Rye KA, Garner B. ATP-binding cassette transporter A7 regulates processing of amyloid precursor protein in vitro. J Neurochem. 2008 Jul;106(2):793-804. PubMed.

External Citations

  1. Alzheimer's Disease Genetics Consortium
  2. ApoE4
  3. ABCA7
  4. AlzGene

Further Reading

Papers

  1. Tan L, Yu JT, Zhang W, Wu ZC, Zhang Q, Liu QY, Wang W, Wang HF, Ma XY, Cui WZ. Association of GWAS-linked loci with late-onset Alzheimer's disease in a northern Han Chinese population. Alzheimers Dement. 2012 Dec 8; PubMed.
  2. Alonso Vilatela ME, López-López M, Yescas-Gómez P. Genetics of Alzheimer's disease. Arch Med Res. 2012 Nov;43(8):622-31. PubMed.
  3. Jin C, Li W, Yuan J, Xu W, Cheng Z. Association of the CR1 polymorphism with late-onset Alzheimer's disease in Chinese Han populations: a meta-analysis. Neurosci Lett. 2012 Oct 3;527(1):46-9. PubMed.
  4. Chung SJ, Lee JH, Kim SY, You S, Kim MJ, Lee JY, Koh J. Association of GWAS Top Hits With Late-onset Alzheimer Disease in Korean Population. Alzheimer Dis Assoc Disord. 2012 Sep 11; PubMed.
  5. Shi H, Belbin O, Medway C, Brown K, Kalsheker N, Carrasquillo M, Proitsi P, Powell J, Lovestone S, Goate A, Younkin S, Passmore P, , Morgan K. Genetic variants influencing human aging from late-onset Alzheimer's disease (LOAD) genome-wide association studies (GWAS). Neurobiol Aging. 2012 Aug;33(8):1849.e5-1849.e18. PubMed.
  6. Swerdlow RH, Corder EH. For Alzheimer disease GWAS, pulling needles from the haystack is just the first step. Neurology. 2012 Jul 17;79(3):204-5. PubMed.

Primary Papers

  1. Nussbaum RL. Genome-wide association studies, Alzheimer disease, and understudied populations. JAMA. 2013 Apr 10;309(14):1527-8. PubMed.
  2. Reitz C, Jun G, Naj A, Rajbhandary R, Vardarajan BN, Wang LS, Valladares O, Lin CF, Larson EB, Graff-Radford NR, Evans D, De Jager PL, Crane PK, Buxbaum JD, Murrell JR, Raj T, Ertekin-Taner N, Logue M, Baldwin CT, Green RC, Barnes LL, Cantwell LB, Fallin MD, Go RC, Griffith P, Obisesan TO, Manly JJ, Lunetta KL, Kamboh MI, Lopez OL, Bennett DA, Hendrie H, Hall KS, Goate AM, Byrd GS, Kukull WA, Foroud TM, Haines JL, Farrer LA, Pericak-Vance MA, Schellenberg GD, Mayeux R, . Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans. JAMA. 2013 Apr 10;309(14):1483-92. PubMed.

Annotate

To make an annotation you must Login or Register.