title: Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.
abstract: The genetic basis of Alzheimer's disease (AD) is complex and heterogeneous. Over 200 highly penetrant pathogenic variants in the genes APP, PSEN1, and PSEN2 cause a subset of early-onset familial AD. On the other hand, susceptibility to late-onset forms of AD (LOAD) is indisputably associated to the ɛ4 allele in the gene APOE, and more recently to variants in more than two-dozen additional genes identified in the large-scale genome-wide association studies (GWAS) and meta-analyses reports. Taken together however, although the heritability in AD is estimated to be as high as 80%, a large proportion of the underlying genetic factors still remain to be elucidated. In this study, we performed a systematic family-based genome-wide association and meta-analysis on close to 15 million imputed variants from three large collections of AD families (~3500 subjects from 1070 families). Using a multivariate phenotype combining affection status and onset age, meta-analysis of the association results revealed three single nucleotide polymorphisms (SNPs) that achieved genome-wide significance for association with AD risk: rs7609954 in the gene PTPRG (P-value=3.98 × 10-8), rs1347297 in the gene OSBPL6 (P-value=4.53 × 10-8), and rs1513625 near PDCL3 (P-value=4.28 × 10-8). In addition, rs72953347 in OSBPL6 (P-value=6.36 × 10-7) and two SNPs in the gene CDKAL1 showed marginally significant association with LOAD (rs10456232, P-value=4.76 × 10-7; rs62400067, P-value=3.54 × 10-7). In summary, family-based GWAS meta-analysis of imputed SNPs revealed novel genomic variants in (or near) PTPRG, OSBPL6, and PDCL3 that influence risk for AD with genome-wide significance.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.|Department of Biostatistics, Harvard T.H Chan School of Public Health, Boston, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Herold
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: B V
authors.initials: BV
authors.lastname: Hooli
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Mullin
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: J T
authors.initials: JT
authors.lastname: Roehr
authors.affiliation: Department of Biomedicine, Bartholins Allé 6, Aarhus, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Mattheisen
authors.affiliation: Computational Sciences, Janssen Research and Development, Pharmaceutical Company of Johnson and Johnson, Spring House, PA, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Parrado
authors.affiliation: Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.|School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology, and Medicine, London, UK.|Platform for Genome Analytics, Institutes of Neurogenetics and Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Bertram
authors.affiliation: Department of Biostatistics, Harvard T.H Chan School of Public Health, Boston, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Lange
authors.affiliation: Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Tanzi
mesh_terms: D017668:Age of Onset; D000368:Aged; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D005190:Family; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D023281:Genomics; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D012359:tRNA Methyltransferases / Q000235:genetics / Q000378:metabolism; D000098825:Oxysterol Binding Proteins
chemical_list: D001057:Apolipoproteins E; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; C498322:PDCL3 protein, human; D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins; D012359:tRNA Methyltransferases; C525110:CDKAL1 protein, human; C516850:PTPRG protein, human; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5
references.citation: Nat Genet. 2009 Mar;41(3):316-23
references.pmid: 19234470
references.citation: Am J Hum Genet. 2004 Feb;74(2):367-9
references.pmid: 14740322
references.citation: J Biol Chem. 2004 Dec 3;279(49):51091-9
references.pmid: 15371430
references.citation: Hum Hered. 2011;71(4):221-33
references.pmid: 21734406
references.citation: Arch Neurol. 2008 Nov;65(11):1518-26
references.pmid: 19001172
references.citation: Am J Hum Genet. 2008 Nov;83(5):623-32
references.pmid: 18976728
references.citation: Arch Gen Psychiatry. 2006 Feb;63(2):168-74
references.pmid: 16461860
references.citation: Neurology. 1997 Jan;48(1):139-47
references.pmid: 9008509
references.citation: Genet Epidemiol. 2012 Dec;36(8):785-96
references.pmid: 22951892
references.citation: CMAJ. 1994 Mar 15;150(6):899-913
references.pmid: 8131123
references.citation: PLoS One. 2006 Dec 20;1:e19
references.pmid: 17183645
references.citation: Biostatistics. 2003 Apr;4(2):195-206
references.pmid: 12925516
references.citation: Bioinformatics. 2010 Sep 1;26(17):2190-1
references.pmid: 20616382
references.citation: Hum Mol Genet. 2009 Oct 15;18(R2):R137-45
references.pmid: 19808789
references.citation: Prog Lipid Res. 2013 Oct;52(4):529-38
references.pmid: 23830809
references.citation: J Biol Chem. 2013 Aug 9;288(32):23171-81
references.pmid: 23792958
references.citation: FEBS Lett. 1993 Dec 28;336(3):417-24
references.pmid: 8282104
references.citation: Adv Genet. 2008;60:219-52
references.pmid: 18358323
references.citation: Nat Genet. 2013 Dec;45(12):1452-8
references.pmid: 24162737
references.citation: Biochem Biophys Res Commun. 1984 Aug 16;122(3):1131-5
references.pmid: 6236805
references.citation: Nat Genet. 2013 Feb;45(2):124-30
references.pmid: 23263488
references.citation: Neurobiol Aging. 2013 Jun;34(6):1653-61
references.pmid: 23273601
references.citation: PLoS Genet. 2006 Aug;2(8):e123
references.pmid: 16895437
references.citation: Am J Hum Genet. 2007 Sep;81(3):559-75
references.pmid: 17701901
references.citation: Hum Mutat. 2010 Jul;31(7):851-7
references.pmid: 20506136
references.citation: Cancer Epidemiol Biomarkers Prev. 2008 Sep;17(9):2208-14
references.pmid: 18768484
references.citation: Nat Genet. 2005 Jul;37(7):683-91
references.pmid: 15937480
references.citation: Nat Rev Genet. 2011 Jun 01;12(7):465-74
references.pmid: 21629274
references.citation: Genet Epidemiol. 2000;19 Suppl 1:S36-42
references.pmid: 11055368
references.citation: PLoS Genet. 2009 Nov;5(11):e1000741
references.pmid: 19956679
references.citation: Int J Obes (Lond). 2013 Apr;37(4):559-67
references.pmid: 22584455
references.citation: PLoS Genet. 2009 Jun;5(6):e1000529
references.pmid: 19543373