Can Genetic Analysis of Putative Blood Alzheimer’s Disease Biomarkers Lead to Identification of Susceptibility Loci?

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

Case Control results.

<p>Panel A; GWAS Manhattan plot for Case Control status. Panel B; QQ plots for the association results for TARCC (left) and ADNI (right). Panel C; LocusZoom plot for the chromosome 19 signal from the meta-analysis. Panels D and E; LocusZoom plots for the chromosome 19 signal in TARCC and ADNI, respectively.</p

Genome-wide significant signals for each endophenotype.

<p>P-values, chromosomal and gene location are presented for each signal from the meta-analyses (Meta) and from the individual (ADNI) and (TARCC) cohorts. P-values are also shown for the association between each endophenotypic signal and age of onset (AOO) and case-control status (CC).</p

Adiponectin results.

<p>Panel A; GWAS Manhattan plot for meta-analysis of Adiponectin. Panel B; QQ plots for the association results for TARCC (left) and ADNI (right). Panel C; LocusZoom plot for the chromosome 3 signal from the meta-analysis. Panels D and E; LocusZoom plots for the chromosome 3 signal in TARCC and ADNI, respectively. Panel F; LocusZoom plot for the chromosome 19 signal from the meta-analysis. Panels G and H; LocusZoom plots for the chromosome 19 signal in TARCC and ADNI, respectively.</p

Associations between published AD SNPs and diagnostic status.

<p>Associations between published AD SNPs and diagnostic status.</p

Factor VII results.

<p>Panel A; GWAS Manhattan plot for the meta-analysis of Factor VII. Panel B; QQ plots for the association results for TARCC (left) and ADNI (right). Panel C; LocusZoom plot for the chromosome 13 signal observed in the meta-analysis. Panels D and E; LocusZoom plots for the chromosome 13 signal in TARCC and ADNI, respectively.</p

Serum protein measures.

<p>Serum protein measures.</p

MCP1 results.

<p>Panel A; GWAS Manhattan plot for meta-analysis of MCP1. Panel B; QQ plots for the association results for TARCC (left) and ADNI (right). Panel C; LocusZoom plot for the chromosome 18 signal from the meta-analysis. Panels D and E; LocusZoom plots for the chromosome 18 signal in TARCC and ADNI, respectively. Panel F; LocusZoom plot for the chromosome 6 signal from the meta-analysis. Panels G and H; LocusZoom plots for the chromosome 6 signal in TARCC and ADNI, respectively.</p