Genome-wide Linkage Analyses of Non-Hispanic White Families Identify Novel Loci for Familial Late-onset Alzheimer's Disease

Overview

Journal Alzheimers Dement

Specialties Neurology
Psychiatry

Date 2015 Sep 15

PMID 26365416

Citations 16

Authors

Brian W Kunkle

James Jaworski

Sandra Barral

Badri Vardarajan

Gary W Beecham

Eden R Martin

Laura S Cantwell

Amanda Partch

Thomas D Bird

Wendy H Raskind

Anita L DeStefano

Regina M Carney

Michael Cuccaro

Jeffrey M Vance

Lindsay A Farrer

Alison M Goate

Tatiana Foroud

Richard P Mayeux

Gerard D Schellenberg

Jonathan L Haines

Margaret A Pericak-Vance

Affiliations

Soon will be listed here.

Abstract

Introduction: Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found.

Methods: We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE ε4 alleles.

Results: Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2-11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2-14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177, and the microRNA Mir_320, whereas IBD analyses implicates an additional gene BCL11B, a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases.

Discussion: Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD.

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References

Lee J, Cheng R, Graff-Radford N, Foroud T, Mayeux R . Analyses of the National Institute on Aging Late-Onset Alzheimer's Disease Family Study: implication of additional loci. Arch Neurol. 2008; 65(11):1518-26. PMC: 2694670. DOI: 10.1001/archneur.65.11.1518. View

Kong A, Cox N . Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet. 1997; 61(5):1179-88. PMC: 1716027. DOI: 10.1086/301592. View

Thornton T, Haines J . PowerTrim: An automated decision support algorithm for preprocessing family-based genetic data. Am J Hum Genet. 2003; 72(5):1280-1. PMC: 1180279. DOI: 10.1086/374823. View

Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E . TREM2 variants in Alzheimer's disease. N Engl J Med. 2012; 368(2):117-27. PMC: 3631573. DOI: 10.1056/NEJMoa1211851. View

Price A, Patterson N, Plenge R, Weinblatt M, Shadick N, Reich D . Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006; 38(8):904-9. DOI: 10.1038/ng1847. View

Maher M, Uricchio L, Torgerson D, Hernandez R . Population genetics of rare variants and complex diseases. Hum Hered. 2013; 74(3-4):118-28. PMC: 3698246. DOI: 10.1159/000346826. View

Matise T, Chen F, Chen W, De La Vega F, Hansen M, He C . A second-generation combined linkage physical map of the human genome. Genome Res. 2007; 17(12):1783-6. PMC: 2099587. DOI: 10.1101/gr.7156307. View

Lambert J, Ibrahim-Verbaas C, Harold D, Naj A, Sims R, Bellenguez C . Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013; 45(12):1452-8. PMC: 3896259. DOI: 10.1038/ng.2802. View

Ventriglia M, Zanardini R, Bonomini C, Zanetti O, Volpe D, Pasqualetti P . Serum brain-derived neurotrophic factor levels in different neurological diseases. Biomed Res Int. 2013; 2013:901082. PMC: 3760208. DOI: 10.1155/2013/901082. View

10.

Cabili M, Trapnell C, Goff L, Koziol M, Tazon-Vega B, Regev A . Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses. Genes Dev. 2011; 25(18):1915-27. PMC: 3185964. DOI: 10.1101/gad.17446611. View

11.

Chu A, Guilianini F, Grallert H, Dupuis J, Ballantyne C, Barratt B . Genome-wide association study evaluating lipoprotein-associated phospholipase A2 mass and activity at baseline and after rosuvastatin therapy. Circ Cardiovasc Genet. 2012; 5(6):676-85. DOI: 10.1161/CIRCGENETICS.112.963314. View

12.

Nagahara A, Merrill D, Coppola G, Tsukada S, Schroeder B, Shaked G . Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med. 2009; 15(3):331-7. PMC: 2838375. DOI: 10.1038/nm.1912. View

13.

Trapnell C, Hendrickson D, Sauvageau M, Goff L, Rinn J, Pachter L . Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat Biotechnol. 2012; 31(1):46-53. PMC: 3869392. DOI: 10.1038/nbt.2450. View

14.

Liu F, Arias-Vasquez A, Sleegers K, Aulchenko Y, Kayser M, Sanchez-Juan P . A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population. Am J Hum Genet. 2007; 81(1):17-31. PMC: 1950931. DOI: 10.1086/518720. View

15.

Chung R, Schmidt M, Morris R, Martin E . CAPL: a novel association test using case-control and family data and accounting for population stratification. Genet Epidemiol. 2010; 34(7):747-55. DOI: 10.1002/gepi.20539. View

16.

Abecasis G, Altshuler D, Auton A, Brooks L, Durbin R, Gibbs R . A map of human genome variation from population-scale sequencing. Nature. 2010; 467(7319):1061-73. PMC: 3042601. DOI: 10.1038/nature09534. View

17.

Pei B, Sisu C, Frankish A, Howald C, Habegger L, Mu X . The GENCODE pseudogene resource. Genome Biol. 2012; 13(9):R51. PMC: 3491395. DOI: 10.1186/gb-2012-13-9-r51. View

18.

Tang B, Di Lena P, Schaffer L, Head S, Baldi P, Thomas E . Genome-wide identification of Bcl11b gene targets reveals role in brain-derived neurotrophic factor signaling. PLoS One. 2011; 6(9):e23691. PMC: 3164671. DOI: 10.1371/journal.pone.0023691. View

19.

Whittemore A, Halpern J . A class of tests for linkage using affected pedigree members. Biometrics. 1994; 50(1):118-27. View

20.

Jonsson T, Atwal J, Steinberg S, Snaedal J, Jonsson P, Bjornsson S . A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012; 488(7409):96-9. DOI: 10.1038/nature11283. View