Rarity of the Alzheimer disease-protective APP A673T variant in the United States.
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Wang Li-San, Naj Adam C, Graham Robert R, Crane Paul K, Kunkle Brian W, Cruchaga Carlos, Murcia Josue D Gonzalez, Cannon-Albright Lisa, Baldwin Clinton T, Zetterberg Henrik, Blennow Kaj, Kukull Walter A, Faber Kelley M, Schupf Nicole, Norton Maria C, Tschanz JoAnn T, Munger Ronald G, Corcoran Christopher D, Rogaeva Ekaterina, Alzheimer's Disease Genetics Consortium, Lin Chiao-Feng, Dombroski Beth A, Cantwell Laura B, Partch Amanda, Valladares Otto, Hakonarson Hakon, St George-Hyslop Peter, Green Robert C, Goate Alison M, Foroud Tatiana M, Carney Regina M, Larson Eric B, Behrens Timothy W, Kauwe John S K, Haines Jonathan L, Farrer Lindsay A, Pericak-Vance Margaret A, Mayeux Richard, Schellenberg Gerard D, National Institute on Aging-Late-Onset Alzheimer’s Disease (NIA-LOAD) Family Study, Albert Marilyn S, Albin Roger L, Apostolova Liana G, Arnold Steven E, Barber Robert, Barmada Michael, Barnes Lisa L, Beach Thomas G, Becker James T, Beecham Gary W, Beekly Duane, Bennett David A, Bigio Eileen H, Bird Thomas D, Blacker Deborah, Boeve Bradley F, Bowen James D, Boxer Adam, Burke James R, Buxbaum Joseph D, Cairns Nigel J, Cao Chuanhai, Carlson Chris S, Carroll Steven L, Chui Helena C, Clark David G, Cribbs David H, Crocco Elizabeth A, DeCarli Charles, DeKosky Steven T, Demirci F Yesim, Dick Malcolm, Dickson Dennis W, Duara Ranjan, Ertekin-Taner Nilufer, Fallon Kenneth B, Farlow Martin R, Ferris Steven, Frosch Matthew P, Galasko Douglas R, Ganguli Mary, Gearing Marla, Geschwind Daniel H, Ghetti Bernardino, Gilbert John R, Glass Jonathan D, Graff-Radford Neill R, Growdon John H, Hamilton Ronald L, Hamilton-Nelson Kara L, Harrell Lindy E, Head Elizabeth, Honig Lawrence S, Hulette Christine M, Hyman Bradley T, Jarvik Gail P, Jicha Gregory A, Jin Lee-Way, Jun Gyungah, Jun Gyungah, Kamboh M Ilyas, Karydas Anna, Kaye Jeffrey A, Kim Ronald, Koo Edward H, Kowall Neil W, Kramer Joel H, LaFerla Frank M, Lah James J, Leverenz James B, Levey Allan I, Li Gei, Lieberman Andrew P, Lopez Oscar L, Lunetta Kathryn L, Lyketsos Constantine G, Mack Wendy J, Marson Daniel C, Martin Eden R, Martiniuk Frank, Mash Deborah C, Masliah Eliezer, McCormick Wayne C, McCurry Susan M, McDavid Andrew N, McKee Ann C, Mesulam W Marsel, Miller Bruce L, Miller Carol A, Miller Joshua W, Montine Thomas J, Morris John C, Murrell Jill R, Olichney John M, Parisi Joseph E, Perry William, Peskind Elaine, Petersen Ronald C, Pierce Aimee, Poon Wayne W, Potter Huntington, Quinn Joseph F, Raj Ashok, Raskind Murray, Reiman Eric M, Reisberg Barry, Reitz Christiane, Ringman John M, Roberson Erik D, Rosen Howard J, Rosenberg Roger N, Sano Mary, Saykin Andrew J, Schneider Julie A, Schneider Lon S, Seeley William W, Smith Amanda G, Sonnen Joshua A, Spina Salvatore, Stern Robert A, Tanzi Rudolph E, Thornton-Wells Tricia A, Trojanowski John Q, Troncoso Juan C, Tsuang Debby W, Van Deerlin Vivianna M, Van Eldik Linda J, Vardarajan Badri N, Vinters Harry V, Vonsattel Jean Paul, Weintraub Sandra, Welsh-Bohmer Kathleen A, Williamson Jennifer, Wishnek Sarah, Woltjer Randall L, Wright Clinton B, Younkin Steven G, Yu Chang-En, Yu Lei
Аннотация
OBJECTIVE: To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden.
DESIGN, SETTING, AND PARTICIPANTS: Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control studies, community-based prospective cohort studies, and studies that ascertained multiplex families from multiple sources.
MAIN OUTCOMES AND MEASURES: Genotypes for the APP A673T variant were determined using the Infinium HumanExome V1 Beadchip (Illumina, Inc) and by TaqMan genotyping (Life Technologies).
RESULTS: The A673T variant genotypes were evaluated in 8943 US AD cases, 10 480 US cognitively normal controls, 862 Swedish AD cases, and 707 Swedish cognitively normal controls. We identified 3 US individuals heterozygous for A673T, including 1 AD case (age at onset, 89 years) and 2 controls (age at last examination, 82 and 77 years). The remaining US samples were homozygous for the alanine (A673) allele. In the Swedish samples, 3 controls were heterozygous for A673T and all AD cases were homozygous for the A673 allele. We also genotyped a US family previously reported to harbor the A673T variant and found a mother-daughter pair, both cognitively normal at ages 72 and 84 years, respectively, who were both heterozygous for A673T; however, all individuals with AD in the family were homozygous for A673.
CONCLUSIONS AND RELEVANCE: The A673T variant is extremely rare in US cohorts and does not play a substantial role in risk for AD in this population. This variant may be primarily restricted to Icelandic and Scandinavian populations.