title: Mutation analysis of the MS4A and TREM gene clusters in a case-control Alzheimer's disease data set.
abstract: Genome wide association studies have identified an association between Alzheimer's disease (AD) and common polymorphisms in the MS4A and TREM loci (each containing a cluster of homologous genes) and should be thoroughly investigated for the presence of potentially functional variations. We conducted a mutation analysis by next generation sequencing of 15 genes within the MS4A and TREM gene clusters; and catalogued rare coding variants detected in a North American data set of 210 cases and 233 controls. Investigation of the 5 homologues genes in the TREM locus revealed potentially damaging rare variants in TREM2, TREML1, TREML2, and TREML4. In agreement with a previous report, we observed a significant enrichment of TREM2-damaging missense substitutions in cases (N = 9; 4.2%) compared with controls (N=2; 0.9%; p = 0.010; after Yates' correction p = 0.022). Among known AD-associated TREM2 substitutions, we detected p.R47H, p.D87N, and p.H157Y affecting both TREM2 isoforms (NM_018965 and NM_001271821). In addition, we identified 2 cases with novel TREM2 variants (p.L205P and p.G219C), which mapped only to the isoform NM_001271821 at the C-terminus. Investigation of the MS4A gene cluster revealed that potentially damaging missense substitutions and loss-of-function variants were twice as frequent in controls (N = 19; 8.2%) than cases (N = 9; 4.3%), generating a nominally significant result (p = 0.047; after Yates' correction p = 0.07). Validation of our observation in large data sets might address the question whether such variants could contribute to the protective effect of the minor alleles of Genome wide association study-significant single nucleotide polymorphisms at the MS4A locus.
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mahdi
authors.initials: M
authors.lastname: Ghani
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Sato
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Erfan Ghani
authors.initials: EG
authors.lastname: Kakhki
authors.affiliation: Computational Biology Core, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
authors.forename: J Raphael
authors.initials: JR
authors.lastname: Gibbs
authors.affiliation: Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Traynor
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Cambridge Institute for Medical Research, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. Electronic address: p.hyslop@utoronto.ca.
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, and Department of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address: ekaterina.rogaeva@utoronto.ca.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Rogaeva
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D066264:Datasets as Topic; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D005810:Multigene Family / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011971:Receptors, Immunologic / Q000235:genetics*; D017421:Sequence Analysis
chemical_list: C574492:MS4A6A protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; C473367:TREML2 protein, human
keywords: Alzheimer's disease; MS4A6A; Mutation; TREM2; TREML2; Targeted sequencing