Journal Article

Pooling/bootstrap-based GWAS (pbGWAS) identifies new loci modifying the age of onset in PSEN1 p.Glu280Ala Alzheimer's disease

Schork, N J, Jones, M, Vélez, J I, Lopez, L, Jaramillo-Elorza, M C, Harper, U, Garcia, G, Martinez, A F, Acosta-Baena, N, Rivera, D, Solomon, B D, Swanson, J M, Kosik, K S, Arcos-Burgos, M, Lopera-Gómez, C M, Lopera, F, Aguirre-Acevedo, D C, Correa, J C, Chandrasekharappa, S C, Henao, E

2013

Overview

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 ( pb GWAS) 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 pb GWAS were confirmed by subsequent individual genotyping. The pb GWAS methodology and the genes it targeted could provide important insights in determining the genetic causes of AD and other complex conditions.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/205/2138 / 631/208/2489/144 / 631/378/1689/1283 / Adult and adolescent clinical studies / Age / Age of Onset / Alanine - genetics / Alzheimer Disease - epidemiology / Alzheimer Disease - genetics / Alzheimer's disease / Behavioral Sciences / Biological and medical sciences / Biological Psychology / Cohort Studies / Databases, Factual - statistics & numerical data / Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases / Disease / DNA sequencing / Female / Founder Effect / Gene Frequency / Genetic aspects / Genetic Predisposition to Disease / Genetic testing / Genome-Wide Association Study / Genomes / Genomics / Genotype / Glutamic Acid - genetics / Humans / Male / Medical research / Medical sciences / Medicine / Medicine & Public Health / Mutation / Mutation - genetics / Neurogenetics / Neurology / Neurosciences / Nucleotide sequencing / Organic mental disorders. Neuropsychology / Original / original-article / Pharmacotherapy / Physiological aspects / Polymorphism, Single Nucleotide / Presenilin-1 - genetics / Psychiatry / Psychology. Psychoanalysis. Psychiatry / Psychopathology. Psychiatry / Quantitative Trait Loci / Research centers / Statistical power / Survival analysis