Abstract Details

Title Resequencing of Confirmed Late-Onset Alzheimer Disease (LOAD) Loci Identifies Multiple Genomic Regions with Potentially Functional Variants

Topic Aging and Dementia

Presentation(s) (-)

Poster/Presentation
Number 004

Objective

Background Besides APOE, GWAS have identified variants in nine genes (CR1, CLU, PICALM, BIN1, EPHA1, MS4A, CD33, CD2AP, and ABCA7) that confer LOAD risk. We resequenced these and surrounding regions in 291 LOAD cases and 103 normal controls.

Design/Methods We performed capture (NimbleGen) and sequencing on Illumina's HiSeq 2000. Target regions included variants in all LD blocks (r2>0.80) overlapping the nine genes, with an average span of 368.3 kilobases. We filtered variants on three criteria: (a) functionality (missense, nonsense, or splice-site variant), (b) potentially damaging (Polyphen-2), and (c) presence in one or more cases and absence in controls. We also examined common and rare variants together grouping by gene and function and using multilocus association testing.

Results We identified 28,894 variants in nine regions. 21,203 were variants of minor allele frequency (MAF) <5% (19,100 with MAF <2%). 14,863 variants (51.4%) were novel. Polyphen-2 rated 247 variants as damaging, of which 180 were novel. Most of the 247 damaging variants were rare (222 with MAF <5%; 209 with <2%), and a subset (n=145; 129 novel) were present in one or more cases while absent in all controls (average MAF = 0.002). Among the rare, potentially damaging functional variants were three missense variants in CR1, four in BIN1, three in CD2AP, six in EPHA1, six in the MS4A region, 14 in ABCA7, and one each in PICALM, CLU, and CD33. Testing identified several clusters of variants associated with LOAD including seven near MS4A (P=0.0049), seven upstream of BIN1 (P=0.0067), and two sets of missense variants near CD33 (one in CD33, P=0.031; one in nearby CLDND2, P=0.045).

Conclusions Resequencing identified rare and novel variants near LOAD susceptibility genes, suggesting that some may contribute to LOAD risk.

Authors/Disclosures
Margaret A. Pericak-Vance, PhD (University of Miami Miller School of Medicine) PRESENTER	Dr. Pericak-Vance has nothing to disclose.
	No disclosure on file
Martin A. Kohli (University of Miami)	No disclosure on file
Sung Lee	No disclosure on file
	No disclosure on file
	No disclosure on file
Patrice Whitehead	No disclosure on file
Bonnie E. Levin, PhD	No disclosure on file
	No disclosure on file
	No disclosure on file
Clinton B. Wright, MD, FAAN (NINDS)	An immediate family member of Dr. Wright has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. An immediate family member of Dr. Wright has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for MARSHALL DENNEHY. The institution of an immediate family member of Dr. Wright has received research support from Oncospace. Dr. Wright has received publishing royalties from a publication relating to health care. An immediate family member of Dr. Wright has received personal compensation in the range of $500-$4,999 for serving as a surveyor with ASTRO.
Stephan Zuchner, MD, FAAN (University of Miami School of Medicine)	Dr. Zuchner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Applied Therapeutics. The institution of Dr. Zuchner has received research support from Muscular Dystrophy Association. The institution of Dr. Zuchner has received research support from CMT Association. Dr. Zuchner has received intellectual property interests from a discovery or technology relating to health care.
Gary W. Beecham, PhD (University of Miami, Hussman Institute for Human Genomics)	The institution of Dr. Beecham has received research support from NIH. The institution of an immediate family member of Dr. Beecham has received research support from NIH.
	No disclosure on file
	No disclosure on file
Jonathan Haines, MD (Vanderbilt University)	No disclosure on file

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