Assessing the Use of Genetic SNPs for Complex Disease Analysis and Discovery of a Role for Apoptosis in Alzheimer's Disease

Anthony J Brookes
Vice-Prefect, Clinical Genomics Coordinator
Center for Genomics Research
Karolinska Institute
Theorells väg 3
S-171 77 Stockholm Sweden
telephone: +46-(0)8-7286630
fax: +46-(0)8-331547
prestype: Platform
presenter: Anthony J Brookes

Center for Genomics Research, Karolinska Institute, 171 77 Stockholm, Sweden.

Everyone hopes or assumes that SNP-based association analysis will help us to understand the genetic basis of complex disease. However, many problems could limit this possibility, e.g., phenotypic and genetic/allelic heterogeneity, population sub-structure, variance in Linkage Disequilibrium (LD), method inadequacies. Despite years of intense study in the field the number of success stories are few - yet it is difficult to draw strong conclusions due to intangible issues such as publication biases, variable experimental design quality, and etiologic differences across population differences.

We have been conducting association analysis in a large-scale manner using an optimal study designed focused strongly upon intragenic SNPs (primarily non-synonymous variants) - assuming that these will comprise and/or be in high LD with pathogenic variants. The study also i) followed a 'pathway-based hypothesis testing' strategy covering high candidature systems to look for clustering of weak-medium signals within pathways, ii) analyzed population-based sets of twins and phenotypic extreme clinical materials from Swedish and Scottish origins, since these will probably have more homogeneous and readily apparent genetic etiologies, and iii) targeted diseases that are well studied biochemically and known to possess high heritability - principally Alzheimer's Disease (AD) and obesity/diabetes.

To enable the above, we i) constructed the Human Genic Bi-Allelic SEquences (HGBASE) database to gather and extensively curate gene-linked SNPs from all public sources, ii) developed Dynamic Allele Specific Hybridization (DASH) for virtually error-free SNP genotyping (>99.9% accuracy) that is robust (less than 1% of assays fail), and cheap (<25c per genotype), and iii) screened 300 AD candidate genes for SNPs, yielding over 500 potential SNPs, many that change amino-acid residues.

Testing over 50 SNPs (60+ candidate AD genes) in the above experimental setting gives a good indication of the many problems and limitations of this approach. From all of these efforts, one very significant new AD association was uncovered (P=0.002), involving a promoter variation in a key apoptosis regulator gene and an interaction with APOE. This result provides strong genetic evidence in support of a role for apoptosis control differences in the causation of AD in many individuals, and may help explain the mechanism by which the E4 allele of APOE mediates an increased AD risk.

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