Abstract
The complexity of human genetic variation has been extended by the observation of abundant and widespread variation in the copy number of submicroscopic DNA segments. The discovery of this novel level of genome organization opened new possibilities concerning the genetic variation that may confer susceptibility to or cause disease. Copy number variants (CNVs) influence gene expression, phenotypic variation and adaptation by altering gene dosage and genome organization. Concordant with the common disease common variant hypothesis these structural variants are now subject to interrogation for disease association. Alzheimer’s disease (AD) is a progressive neurodegenerative disease with an estimated heritability of 60–80 %. Large scale genome-wide association studies (GWAS) using high frequency single nucleotide polymorphism (SNP) variants identified ten loci which do not account for the measured heritability. To find the missing heritability systematic assessment of all mutational mechanisms needs to be performed. Between the powerful SNP-GWAS studies and the planned Whole Genome Sequencing projects the contribution of copy number variation (CNV) to the genetic architecture of AD needs to be studied fully.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Kukull WA, Higdon R, Bowen JD et al (2002) Dementia and Alzheimer disease incidence: a prospective cohort study. Arch Neurol 59:1737–1746
Gatz M, Pedersen NL, Berg S et al (1997) Heritability for Alzheimer’s disease: the study of dementia in Swedish twins. J Gerontol A Biol Sci Med Sci 52:M117–M125
Naj AC, Jun G, Beecham GW et al (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset alzheimer’s disease. Nat Genet 43:436–441
Feuk L, Carson AR, Scherer SW (2006) Structural variation in the human genome. Nat Rev Genet 7:85–97
Redon R, Ishikawa S, Fitch KR et al (2006) Global variation in copy number in the human genome. Nature 444:444–454
Stranger BE, Forrest MS, Dunning M et al (2007) Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315:848–853
Rovelet-Lecrux A, Hannequin D, Raux G et al (2006) APP locus duplication causes autosomal dominant early-onset alzheimer disease with cerebral amyloid angiopathy. Nat Genet 38:24–26
Singleton AB, Farrer M, Johnson J et al (2003) alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302:841
Padiath QS, Saigoh K, Schiffmann R et al (2006) Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat Genet 38:1114–1123
Chapman J, Rees E, Harold D et al (2013) A genome-wide study shows a limited contribution of rare copy number variants to Alzheimer’s disease risk. Hum Mol Genet 22:816–824
Swaminathan S, Huentelman MJ, Corneveaux JJ et al (2012) Analysis of copy number variation in Alzheimer’s disease in a cohort of clinically characterized and neuropathologically verified individuals. PLoS One 7:e50640
Swaminathan S, Kim S, Shen L et al (2011) Genomic copy number analysis in Alzheimer’s disease and mild cognitive impairment: an ADNI study. Int J Alzheimers Dis 2011:729478
Swaminathan S, Shen L, Kim S et al (2012) Analysis of copy number variation in Alzheimer’s disease: the NIALOAD/NCRAD family study. Curr Alzheimer Res 9:801–814
Heinzen EL, Need AC, Hayden KM et al (2010) Genome-wide scan of copy number variation in late-onset alzheimer’s disease. J Alzheimers Dis 19:69–77
Ghani M, Pinto D, Lee JH et al (2012) Genome-wide survey of large rare copy number variants in Alzheimer’s disease among Caribbean hispanics. G3 (Bethesda) 2:71–78
Shaw CA, Li Y, Wiszniewska J et al (2011) Olfactory copy number association with age at onset of Alzheimer disease. Neurology 76:1302–1309
Szigeti K, Lal D, Li Y et al (2013) Genome-wide scan for copy number variation association with age at onset of Alzheimer’s disease. J Alzheimers Dis 33:517–523
Conrad DF, Keebler JE, DePristo MA et al (2011) Variation in genome-wide mutation rates within and between human families. Nat Genet 43:712–714
McConnell MJ, Lindberg MR, Brennand KJ et al (2013) Mosaic copy number variation in human neurons. Science 342:632–637
Pinto D, Darvishi K, Shi X et al (2011) Comprehensive assessment of array-based platforms and calling algorithms for detection of copy number variants. Nat Biotechnol 29:512–520
Harold D, Abraham R, Hollingworth P et al (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41:1088–1093
Seshadri S, Fitzpatrick AL, Ikram MA et al (2010) Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303:1832–1840
Lambert JC, Heath S, Even G et al (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41:1094–1099
Ku CS, Loy EY, Pawitan Y et al (2010) The pursuit of genome-wide association studies: where are we now? J Hum Genet 55:195–206
Florez JC (2008) Clinical review: the genetics of type 2 diabetes: a realistic appraisal in 2008. J Clin Endocrinol Metab 93:4633–4642
Nicolae DL, Gamazon E, Zhang W et al (2010) Trait-associated SNPs are more likely to be eQTLs: annotation to enhance discovery from GWAS. PLoS Genet 6:e1000888
Carter NP (2007) Methods and strategies for analyzing copy number variation using DNA microarrays. Nat Genet 39(7 Suppl):S16–S21
Scherer SW, Lee C, Birney E et al (2007) Challenges and standards in integrating surveys of structural variation. Nat Genet 39(7 Suppl):S7–S15
Duan J, Zhang JG, Deng HW, Wang YP (2013) Comparative studies of copy number variation detection methods for next-generation sequencing technologies. PLoS One 8:e59128
Acknowledgements
This work was supported by an Alzheimer Association New Investigator Research Grant to K.S.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer Science+Business Media New York
About this protocol
Cite this protocol
Szigeti, K. (2016). New Genome-Wide Methods for Elucidation of Candidate Copy Number Variations (CNVs) Contributing to Alzheimer’s Disease Heritability. In: Castrillo, J., Oliver, S. (eds) Systems Biology of Alzheimer's Disease. Methods in Molecular Biology, vol 1303. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2627-5_19
Download citation
DOI: https://doi.org/10.1007/978-1-4939-2627-5_19
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-2626-8
Online ISBN: 978-1-4939-2627-5
eBook Packages: Springer Protocols