Paper Alert: New Alzheimer’s Genes Published
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A meta-analysis of four large Alzheimer’s genome-wide association studies has doubled the number of genetic loci strongly linked to the disease. The findings were previously reported at the Alzheimer’s Association International Conference, held July 13–18 in Boston (see ARF related news story), and are now formally published in the October 27 Nature Genetics. Hundreds of researchers in the International Genomics of Alzheimer’s Project (IGAP) collaborated on the study, which turned up 11 new loci associated with AD risk. The study also confirmed nine previous GWAS hits, failing to replicate only CD33 among the AlzGene Top Results.
Although the GWAS results pinpoint regions of the genome associated with AD, researchers still need to identify the genetic variants in those regions that actually cause disease. Candidate genes near the susceptibility loci participate in many pathways previously implicated in Alzheimer’s, including cholesterol metabolism, intracellular trafficking, and immunity. The findings may help point to new therapeutic targets, said author Julie Williams at Cardiff University, U.K.
GWAS typically find common variants with small effects. The new loci contribute slightly less risk than previous GWAS hits BIN1, CLU, and PICALM. For those genes, the percentage of disease in the population estimated to be due to each runs between 5 and 8 percent. For the new genes, the population-attributable fractions are mostly between 2 and 5 percent. To find rare variants with larger effects, like the recently identified one in the immune receptor TREM2 (see ARF related news story), researchers need to look at families with earlier-onset sporadic AD, Williams said.—Madolyn Bowman Rogers
References
News Citations
- Pooled GWAS Reveals New Alzheimer’s Genes and Pathways
- Enter the New Alzheimer’s Gene: TREM2 Variant Triples Risk
External Citations
Further Reading
News
- In Shout-Out for Community Studies, Vantaa Finds Protective Mutation
- By Digging Tau, GWAS Unearths TREM (Again), Plus New Leads
- AD GWAS in African Americans Confirms, Reshuffles AlzGene List
- Protective Microglial Gene Variant Promotes Phagocytosis
- RNA Sequencing Helps Identify Functional Variants from GWAS
- Vienna: New Genes, Anyone? ICAD Saves Best for Last
- Vienna: In Genetics, Bigger Is Better—Data Sharing Nets Three New Hits
- LOADing Up—Largest GWAS to Date Confirms Two, Adds Two Risk Genes
- Repeat Offenders—CLU, CR1, PICALM Hold Up in Association Studies
- Barcelona: What Lies Beyond Genomewide Association Studies?
- Large Genetic Analysis Pays Off With New AD Risk Genes
- AlzGene Reorg—"Top Results" Reduced to Elite Few
- Late- and Early Onset AD—Not So Distant at Genetic Level
- GWAS and Anatomy—Pooled Data Finger Genes Driving Brain Size, IQ
- GWAS Mega-Meta Yields More Risk Genes, BIN1 Binds Tau?
- ENCODE Turns Human Genome From Sequence to Machine
- Newly Mapped DNA Elements Help Interpret GWAS
- Genetics Project Update: Over 1,000 Genomes and Counting
- Getting a CLU—Does Genetic Risk Factor Mediate Aβ Toxicity?
- First Plaque-Based GWAS Revives Enzyme Link
Primary Papers
- Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thorton-Wells TA, Jones N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, Kamatani Y, Lin CF, Gerrish A, Schmidt H, Kunkle B, Dunstan ML, Ruiz A, Bihoreau MT, Choi SH, Reitz C, Pasquier F, Cruchaga C, Craig D, Amin N, Berr C, Lopez OL, De Jager PL, Deramecourt V, Johnston JA, Evans D, Lovestone S, Letenneur L, Morón FJ, Rubinsztein DC, Eiriksdottir G, Sleegers K, Goate AM, Fiévet N, Huentelman MW, Gill M, Brown K, Kamboh MI, Keller L, Barberger-Gateau P, McGuiness B, Larson EB, Green R, Myers AJ, Dufouil C, Todd S, Wallon D, Love S, Rogaeva E, Gallacher J, St George-Hyslop P, Clarimon J, Lleo A, Bayer A, Tsuang DW, Yu L, Tsolaki M, Bossù P, Spalletta G, Proitsi P, Collinge J, Sorbi S, Sanchez-Garcia F, Fox NC, Hardy J, Deniz Naranjo MC, Bosco P, Clarke R, Brayne C, Galimberti D, Mancuso M, Matthews F, European Alzheimer's Disease Initiative (EADI), Genetic and Environmental Risk in Alzheimer's Disease, Alzheimer's Disease Genetic Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology, Moebus S, Mecocci P, Del Zompo M, Maier W, Hampel H, Pilotto A, Bullido M, Panza F, Caffarra P, Nacmias B, Gilbert JR, Mayhaus M, Lannefelt L, Hakonarson H, Pichler S, Carrasquillo MM, Ingelsson M, Beekly D, Alvarez V, Zou F, Valladares O, Younkin SG, Coto E, Hamilton-Nelson KL, Gu W, Razquin C, Pastor P, Mateo I, Owen MJ, Faber KM, Jonsson PV, Combarros O, O'Donovan MC, Cantwell LB, Soininen H, Blacker D, Mead S, Mosley TH Jr, Bennett DA, Harris TB, Fratiglioni L, Holmes C, de Bruijn RF, Passmore P, Montine TJ, Bettens K, Rotter JI, Brice A, Morgan K, Foroud TM, Kukull WA, Hannequin D, Powell JF, Nalls MA, Ritchie K, Lunetta KL, Kauwe JS, Boerwinkle E, Riemenschneider M, Boada M, Hiltuenen M, Martin ER, Schmidt R, Rujescu D, Wang LS, Dartigues JF, Mayeux R, Tzourio C, Hofman A, Nöthen MM, Graff C, Psaty BM, Jones L, Haines JL, Holmans PA, Lathrop M, Pericak-Vance MA, Launer LJ, Farrer LA, van Duijn CM, Van Broeckhoven C, Moskvina V, Seshadri S, Williams J, Schellenberg GD, Amouyel P, Wang J, Uitterlinden AG, Rivadeneira F, Koudstgaal PJ, Longstreth WT Jr, Becker JT, Kuller LH, Lumley T, Rice K, Garcia M, Aspelund T, Marksteiner JJ, Dal-Bianco P, Töglhofer AM, Freudenberger P, Ransmayr G, Benke T, Toeglhofer AM, Bressler J, Breteler MM, Fornage M, Hernández I, Rosende Roca M, Ana Mauleón M, Alegrat M, Ramírez-Lorca R, González-Perez A, Chapman J, Stretton A, Morgan A, Kehoe PG, Medway C, Lord J, Turton J, Hooper NM, Vardy E, Warren JD, Schott JM, Uphill J, Ryan N, Rossor M, Ben-Shlomo Y, Makrina D, Gkatzima O, Lupton M, Koutroumani M, Avramidou D, Germanou A, Jessen F, Riedel-Heller S, Dichgans M, Heun R, Kölsch H, Schürmann B, Herold C, Lacour A, Drichel D, Hoffman P, Kornhuber J, Gu W, Feulner T, van den Bussche H, Lawlor B, Lynch A, Mann D, Smith AD, Warden D, Wilcock G, Heuser I, Wiltgang J, Frölich L, Hüll M, Mayo K, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Singleton AB, Guerreiro R, Jöckel KH, Klopp N, Wichmann HE, Dickson DW, Graff-Radford NR, Ma L, Bisceglio G, Fisher E, Warner N, Pickering-Brown S. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013 Dec;45(12):1452-8. Epub 2013 Oct 27 PubMed.
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