title: A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk.
abstract: We assessed the role of rare copy number variants (CNVs) in Alzheimer's disease (AD) using intensity data from 3260 AD cases and 1290 age-matched controls from the genome-wide association study (GWAS) conducted by the Genetic and Environmental Risk for Alzheimer's disease Consortium (GERAD). We did not observe a significant excess of rare CNVs in cases, although we did identify duplications overlapping APP and CR1 which may be pathogenic. We looked for an excess of CNVs in loci which have been highlighted in previous AD CNV studies, but did not replicate previous findings. Through pathway analyses, we observed suggestive evidence for biological overlap between single nucleotide polymorphisms and CNVs in AD susceptibility. We also identified that our sample of elderly controls harbours significantly fewer deletions >1 Mb than younger control sets in previous CNV studies on schizophrenia and bipolar disorder (P = 8.9 × 10(-4) and 0.024, respectively), raising the possibility that healthy elderly individuals have a reduced rate of large deletions. Thus, in contrast to diseases such as schizophrenia, autism and attention deficit/hyperactivity disorder, CNVs do not appear to make a significant contribution to the development of AD.
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Jade
authors.initials: J
authors.lastname: Chapman
authors.forename: Elliott
authors.initials: E
authors.lastname: Rees
authors.forename: Denise
authors.initials: D
authors.lastname: Harold
authors.forename: Dobril
authors.initials: D
authors.lastname: Ivanov
authors.forename: Amy
authors.initials: A
authors.lastname: Gerrish
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sims
authors.forename: Paul
authors.initials: P
authors.lastname: Hollingworth
authors.forename: Alexandra
authors.initials: A
authors.lastname: Stretton
authors.forename: Peter
authors.initials: P
authors.lastname: Holmans
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Michael C
authors.initials: MC
authors.lastname: O'Donovan
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
authors.forename: George
authors.initials: G
authors.lastname: Kirov
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D016022:Case-Control Studies; D056915:DNA Copy Number Variations; D020440:Gene Duplication; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D017463:Receptors, Complement 3b / Q000235:genetics; D012307:Risk Factors
chemical_list: D016564:Amyloid beta-Protein Precursor; C509991:CR1 protein, human; D017463:Receptors, Complement 3b