An intronic PICALM polymorphism, rs588076, is associated with allelic expression of a PICALM isoform

Molecular Neurodegeneration

Steven Estus²  David W Fardo³  Steven Younkin¹  Christopher Medway¹  Ishita Parikh² 

[1] Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA;Departments of Physiology, Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone St., Lexington, KY 40536, USA;Biostatistics, Sanders-Brown Center on Aging, University of Kentucky, 800 S. Limestone St., Lexington, KY 40536, USA

关键词: Single nucleotide polymorphism;    Allelic expression imbalance;    Next-generation sequencing;    Alzheimer’s disease;    PICALM;   

Others  :  1138750
DOI  :  10.1186/1750-1326-9-32

 received in 2014-07-24, accepted in 2014-08-21,  发布年份 2014

【 摘 要 】

Background

Although genome wide studies have associated single nucleotide polymorphisms (SNP)s near PICALM with Alzheimer’s disease (AD), the mechanism underlying this association is unclear. PICALM is involved in clathrin-mediated endocytosis and modulates Aß clearance in vitro. Comparing allelic expression provides the means to detect cis-acting regulatory polymorphisms. Thus, we evaluated whether PICALM showed allele expression imbalance (AEI) and whether this imbalance was associated with the AD-associated polymorphism, rs3851179.

Results

We measured PICALM allelic expression in 42 human brain samples by using next-generation sequencing. Overall, PICALM demonstrated equal allelic expression with no detectable influence by rs3851179. A single sample demonstrated robust global PICALM allelic expression imbalance (AEI), i.e., each of the measured isoforms showed AEI. Moreover, the PICALM isoform lacking exons 18 and 19 (D18-19 PICALM) showed significant AEI in a subset of individuals. Sequencing these individuals and subsequent genotyping revealed that rs588076, located in PICALM intron 17, was robustly associated with this imbalance in D18-19 PICALM allelic expression (p = 9.54 x 10^-5). This polymorphism has been associated previously with systolic blood pressure response to calcium channel blocking agents. To evaluate whether this polymorphism was associated with AD, we genotyped 3269 individuals and found that rs588076 was modestly associated with AD. However, when both the primary AD SNP rs3851179 was added to the logistic regression model, only rs3851179 was significantly associated with AD.

Conclusions

PICALM expression shows no evidence of AEI associated with rs3851179. Robust global AEI was detected in one sample, suggesting the existence of a rare SNP that strongly modulates PICALM expression. AEI was detected for the D18-19 PICALM isoform, and rs588076 was associated with this AEI pattern. Conditional on rs3851179, rs588076 was not associated with AD risk, suggesting that D18-19 PICALM is not critical in AD. In summary, this analysis of PICALM allelic expression provides novel insights into the genetics of PICALM expression and AD risk.

【 授权许可】

   
2014 Parikh et al.; licensee BioMed Central Ltd.

【 图 表 】

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