Expression quantitative trait loci regulate HNF4A and PTBP1 expression in human brains.

Parkinson’s disease (PD) is the second most common neurodegenerative disease in the elderly. Santiago and Potashkin (1) recently performed a network-based metaanalysis of four independent microarray datasets and identified hepatocyte nuclear factor 4 alpha (HNF4A) and polypyrimidine tract binding protein 1 (PTBP1) to be the longitudinally dynamic biomarkers for PD. They found that HNF4A is a central regulatory hub gene up-regulated in blood of PD patients and PTBP1 is the most downregulated gene (1). It is reported that a kind of genetic variants [expression quantitative trait loci (eQTLs)] may modify brain gene expression and influence risk for human diseases (2). In the postgenome era, it is a fundamental challenge to understand and annotate the consequences of eQTLs in the context of human tissues (3). Here, we investigate whether the expression of HNF4A and PTBP1 is regulated by common genetic variants using two eQTLs datasets. The first dataset included 600 tissues from 150 neurologically normal individuals in four human brain regions including cerebellum (CB), frontal cortex (FC), pons (PONS), and temporal cortex (TC) (3). The second dataset consisted of 1,647 tissues from 549 brains of 376 late-onset Alzheimer’s disease (LOAD) patients and 173 nondemented healthy controls, as well as 582 tissues from 194 Huntington’s disease (HD) patients in three human brain regions including dorsolateral prefrontal cortex (PFC), visual cortex (VC), and CB (4). In dataset 1, we found that PTBP1 expression was regulated by a trans-regulatory single nucleotide polymorphism (SNP) rs11146131 in Janus kinase and microtubule interacting protein 3 (JAKMIP3) gene with P = 2.02E-08 in PONS (3). In dataset 2, we identified that cis-regulatory SNPs rs6031598, rs6031596, rs3212199, rs6130595, and rs2075960 regulated HNF4A expression in kinds of conditions and tissues (Table 1). Collectively, using two QTLs datasets from large-scale human brain tissues in kinds of conditions, we showed that the expression of HNF4A and PTBP1 was regulated by eQTLs, which may be useful for understanding the dysregulation of both genes in PD patients.