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Novel susceptibility loci for Alzheimer's disease.

ABSTRACT: Late-onset Alzheimer's disease (AD), a highly prevalent neurodegenerative disorder characterized by progressive deterioration in cognition, function and behavior terminating in incapacity and death, is a clinically and pathologically heterogeneous disease with a substantial heritable component. During the past 5 years, the technological developments in next-generation high-throughput genome technologies have led to the identification of more than 20 novel susceptibility loci for AD, and have implicated specific pathways in the disease, in particular intracellular trafficking/endocytosis, inflammation and immune response and lipid metabolism. These observations have significantly advanced our understanding of underlying pathogenic mechanisms and potential therapeutic targets. This review article summarizes these recent advances in AD genomics and discusses the value of identified susceptibility loci for diagnosis and prognosis of AD.

SUBMITTER: Reitz C

PROVIDER: S-EPMC4820289 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Novel susceptibility loci for Alzheimer's disease.

Reitz Christiane C

Future neurology 20151201 6

Late-onset Alzheimer's disease (AD), a highly prevalent neurodegenerative disorder characterized by progressive deterioration in cognition, function and behavior terminating in incapacity and death, is a clinically and pathologically heterogeneous disease with a substantial heritable component. During the past 5 years, the technological developments in next-generation high-throughput genome technologies have led to the identification of more than 20 novel susceptibility loci for AD, and have imp ...[more]

PMID: 27057151

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Project description:Although 24 Alzheimer's disease (AD) risk loci have been reliably identified, a large portion of the predicted heritability for AD remains unexplained. It is expected that additional loci of small effect will be identified with an increased sample size. However, the cost of a significant increase in Case-Control sample size is prohibitive. The current study tests whether exploring the genetic basis of endophenotypes, in this case based on putative blood biomarkers for AD, can accelerate the identification of susceptibility loci using modest sample sizes. Each endophenotype was used as the outcome variable in an independent GWAS. Endophenotypes were based on circulating concentrations of proteins that contributed significantly to a published blood-based predictive algorithm for AD. Endophenotypes included Monocyte Chemoattractant Protein 1 (MCP1), Vascular Cell Adhesion Molecule 1 (VCAM1), Pancreatic Polypeptide (PP), Beta2 Microglobulin (B2M), Factor VII (F7), Adiponectin (ADN) and Tenascin C (TN-C). Across the seven endophenotypes, 47 SNPs were associated with outcome with a p-value ?1x10(-7). Each signal was further characterized with respect to known genetic loci associated with AD. Signals for several endophenotypes were observed in the vicinity of CR1, MS4A6A/MS4A4E, PICALM, CLU, and PTK2B. The strongest signal was observed in association with Factor VII levels and was located within the F7 gene. Additional signals were observed in MAP3K13, ZNF320, ATP9B and TREM1. Conditional regression analyses suggested that the SNPs contributed to variation in protein concentration independent of AD status. The identification of two putatively novel AD loci (in the Factor VII and ATP9B genes), which have not been located in previous studies despite massive sample sizes, highlights the benefits of an endophenotypic approach for resolving the genetic basis for complex diseases. The coincidence of several of the endophenotypic signals with known AD loci may point to novel genetic interactions and should be further investigated.

Project description:Identifying genetic risk factors underpinning different aspects of Alzheimer's disease has the potential to provide important insights into pathogenesis. Moving away from simple case-control definitions, there is considerable interest in using quantitative endophenotypes, such as those derived from imaging as outcome measures. Previous genome-wide association studies of imaging-derived biomarkers in sporadic late-onset Alzheimer's disease focused only on phenotypes derived from single imaging modalities. In contrast, we computed a novel multi-modal neuroimaging phenotype comprising cortical amyloid burden and bilateral hippocampal volume. Both imaging biomarkers were used as input to a disease progression modelling algorithm, which estimates the biomarkers' long-term evolution curves from population-based longitudinal data. Among other parameters, the algorithm computes the shift in time required to optimally align a subjects' biomarker trajectories with these population curves. This time shift serves as a disease progression score and it was used as a quantitative trait in a discovery genome-wide association study with n = 944 subjects from the Alzheimer's Disease Neuroimaging Initiative database diagnosed as Alzheimer's disease, mild cognitive impairment or healthy at the time of imaging. We identified a genome-wide significant locus implicating LCORL (rs6850306, chromosome 4; P = 1.03 × 10-8). The top variant rs6850306 was found to act as an expression quantitative trait locus for LCORL in brain tissue. The clinical role of rs6850306 in conversion from healthy ageing to mild cognitive impairment or Alzheimer's disease was further validated in an independent cohort comprising healthy, older subjects from the National Alzheimer's Coordinating Center database. Specifically, possession of a minor allele at rs6850306 was protective against conversion from mild cognitive impairment to Alzheimer's disease in the National Alzheimer's Coordinating Center cohort (hazard ratio = 0.593, 95% confidence interval = 0.387-0.907, n = 911, PBonf = 0.032), in keeping with the negative direction of effect reported in the genome-wide association study (βdisease progression score = -0.07 ± 0.01). The implicated locus is linked to genes with known connections to Alzheimer's disease pathophysiology and other neurodegenerative diseases. Using multimodal imaging phenotypes in association studies may assist in unveiling the genetic drivers of the onset and progression of complex diseases.

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Novel susceptibility loci for Alzheimer's disease.

Publications

Novel susceptibility loci for Alzheimer's disease.

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