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 down-regulated 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).
Table 1.
cis-Regulatory SNPs regulating HNF4A in kinds of conditions and tissues
| Condition | Tissue | Platform | rsID | P value | N (sample) | cis eSNP chr | eSNP pos |
| HD | PFC | IL650 | rs6031598 | 5.84E-07 | 147 | 20 | 42489563 |
| HD | PFC | PL300 | rs6031596 | 7.60E-06 | 74 | 20 | 42488285 |
| HD | PFC | IL650 | rs6031598 | 1.43E-03 | 147 | 20 | 42489563 |
| HD | PFC | PL300 | rs6031596 | 1.66E-02 | 74 | 20 | 42488285 |
| LOAD | PFC | IL650 | rs6031598 | 1.18E-06 | 288 | 20 | 42489563 |
| LOAD | PFC | IL650 | rs6031598 | 3.32E-05 | 288 | 20 | 42489563 |
| LOAD | VC | IL650 | rs6031598 | 4.20E-05 | 178 | 20 | 42489563 |
| Norm | PFC | IL650 | rs3212199 | 2.65E-11 | 146 | 20 | 42479459 |
| Norm | PFC | IL650 | rs6031598 | 1.84E-08 | 146 | 20 | 42489563 |
| Tissue | PFC | IL650 | rs6031598 | 1.96E-21 | 583 | 20 | 42489563 |
| Tissue | PFC | PL300 | rs6031596 | 6.28E-10 | 347 | 20 | 42488285 |
| Tissue | PFC | IL650 | rs6031598 | 3.23E-25 | 583 | 20 | 42489563 |
| Tissue | PFC | PL300 | rs6031596 | 3.24E-07 | 347 | 20 | 42488285 |
| Tissue | VC | IL650 | rs6031598 | 1.99E-06 | 409 | 20 | 42489563 |
| Tissue | VC | IL650 | rs3212199 | 4.12E-06 | 409 | 20 | 42479459 |
| Tissue | CB | PL300 | rs6130595 | 4.20E-05 | 256 | 20 | 42421167 |
| Tissue | CB | PL300 | rs2075960 | 1.13E-05 | 255 | 20 | 42981091 |
chr, Chromosome; HD, Huntington’s disease; IL650, Illumina 650K; LOAD, late-onset Alzheimer’s disease; Norm, nondemented; PL300, Perlegen 300K; pos, position; Tissue, all conditions per region.
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.
Acknowledgments
This work was supported by funding from the National Nature Science Foundation of China (Grant 81300945) and the National High-Tech Research and Development Project of China (Grant 2013AA020106).
Footnotes
The authors declare no conflict of interest.
References
- 1.Santiago JA, Potashkin JA. Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson’s disease. Proc Natl Acad Sci USA. 2015;112(7):2257–2262. doi: 10.1073/pnas.1423573112. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Zou F, et al. Alzheimer’s Disease Genetics Consortium Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants. PLoS Genet. 2012;8(6):e1002707. doi: 10.1371/journal.pgen.1002707. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Gibbs JR, et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet. 2010;6(5):e1000952. doi: 10.1371/journal.pgen.1000952. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Zhang B, et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell. 2013;153(3):707–720. doi: 10.1016/j.cell.2013.03.030. [DOI] [PMC free article] [PubMed] [Google Scholar]