Abstract：
:The literature on GWAS (genome-wide association studies) data suggests that very large sample sizes (for example, 50,000 cases and 50,000 controls) may be required to detect significant associations of genomic regions for complex disorders such as Alzheimer's disease (AD). Because of the challenges of obtaining such large cohorts, we describe here a novel sequential strategy that combines pooling of DNA and bootstrapping (pbGWAS) in order to significantly increase the statistical power and exponentially reduce expenses. We applied this method to a very homogeneous sample of patients belonging to a unique and clinically well-characterized multigenerational pedigree with one of the most severe forms of early onset AD, carrying the PSEN1 p.Glu280Ala mutation (often referred to as E280A mutation), which originated as a consequence of a founder effect. In this cohort, we identified novel loci genome-wide significantly associated as modifiers of the age of onset of AD (CD44, rs187116, P=1.29 × 10⁻¹²; NPHP1, rs10173717, P=1.74 × 10⁻¹²; CADPS2, rs3757536, P=1.54 × 10⁻¹⁰; GREM2, rs12129547, P=1.69 × 10⁻¹³, among others) as well as other loci known to be associated with AD. Regions identified by pbGWAS were confirmed by subsequent individual genotyping. The pbGWAS methodology and the genes it targeted could provide important insights in determining the genetic causes of AD and other complex conditions.
journal_name
Mol Psychiatryjournal_title
Molecular psychiatryauthors
Vélez JI,Chandrasekharappa SC,Henao E,Martinez AF,Harper U,Jones M,Solomon BD,Lopez L,Garcia G,Aguirre-Acevedo DC,Acosta-Baena N,Correa JC,Lopera-Gómez CM,Jaramillo-Elorza MC,Rivera D,Kosik KS,Schork NJ,Swanson JM,Lopdoi
10.1038/mp.2012.81subject
Has Abstractpub_date
2013-05-01 00:00:00pages
568-75issue
5eissn
1359-4184issn
1476-5578pii
mp201281journal_volume
18pub_type
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