A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk

TY - JOUR

T1 - A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk

AU - Chapman, Jade

AU - Rees, Elliott

AU - Harold, Denise

AU - Ivanov, Dobril

AU - Gerrish, Amy

AU - Sims, Rebecca

AU - Hollingworth, Paul

AU - Stretton, Alexandra

AU - Holmans, Peter

AU - Owen, Michael J

AU - O'Donovan, Michael C

AU - Williams, Julie

AU - Kirov, George

AU - GERAD1 Consortium

AU - van den Bussche, Hendrik

PY - 2013/2/15

Y1 - 2013/2/15

N2 - 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.

AB - 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.

KW - Aged

KW - Alzheimer Disease

KW - Amyloid beta-Protein Precursor

KW - Case-Control Studies

KW - DNA Copy Number Variations

KW - Gene Duplication

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome, Human

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Polymorphism, Single Nucleotide

KW - Receptors, Complement 3b

KW - Risk Factors

U2 - 10.1093/hmg/dds476

DO - 10.1093/hmg/dds476

M3 - SCORING: Journal article

C2 - 23148125

VL - 22

SP - 816

EP - 824

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 4

ER -