Assessment of Alzheimer's disease case-control associations using family-based methods.
The genetics of Alzheimer's disease (AD) is heterogeneous and remains only ill-defined. We have recently created a freely available and continuously updated online database (AlzGene; http://www.alzgene.org ) for which we collect all published genetic association studies in AD and perform systematic meta-analyses on all polymorphisms with sufficient genotype data. In this study, we tested 27 genes (ACE, BDNF, CH25H, CHRNB2, CST3, CTSD, DAPK1, GALP, hCG2039140, IL1B, LMNA, LOC439999, LOC651924, MAPT, MTHFR, MYH13, PCK1, PGBD1, PRNP, PSEN1, SORCS1, SORL1, TF, TFAM, TNK1, GWA_14q32.13, and GWA_7p15.2), all showing significant association with AD risk in the AlzGene meta-analyses, in a large collection of family-based samples comprised of 4,180 subjects from over 1,300 pedigrees. Overall, we observe significant association with risk for AD and polymorphisms in ACE, CHRNB2, TF, and an as yet uncharacterized locus on chromosome 7p15.2 [rs1859849]. For all four loci, the association was observed with the same alleles as in the AlzGene meta-analyses. The convergence of case-control and family-based findings suggests that these loci currently represent the most promising AD gene candidates. Further fine-mapping and functional analyses are warranted to elucidate the potential biochemical mechanisms and epidemiological relevance of these genes.
Schjeide
Brit-Maren M
BM
MassGeneral Institute for Neurodegenerative Disease (MIND), Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
McQueen
Matthew B
MB
Mullin
Kristina
K
DiVito
Jason
J
Hogan
Meghan F
MF
Parkinson
Michele
M
Hooli
Basavaraj
B
Lange
Christoph
C
Blacker
Deborah
D
Tanzi
Rudolph E
RE
Bertram
Lars
L
D000544:Alzheimer Disease / Q000235:genetics*; D016022:Case-Control Studies; D030541:Databases, Genetic; D005006:Ethnicity / Q000235:genetics; D005190:Family; D005820:Genetic Testing; D005838:Genotype; D006801:Humans