An important unresolved general question in human genetics is how the majority of common genomic variation, much of which is associated with common diseases, changes gene function. Most variants that have been found in association with neurodegenerative diseases, for example, do not change protein coding regions. One reasonable hypothesis is that common variants change how genes are regulated in specific cells, perhaps under specific circumstances. We have addressed this by examining mRNA and miRNA expression, using gene expression microarrays, in the brains of a number of individuals who have been genotypes at a large number of genomic loci, tagged using using single nucleotide polymorphisms (SNPs). We find that for many genes, there is an association between genotype and gene expression and that this relationship is dependent on the physical distance between the SNP and the gene that is expressed. When we specifically examine genetic variants that are robustly associated with neurodegenerative diseases, we find that these impact gene expression in predictable and robust ways. This data begins to define the relationships between common variants and common disorders. Many such genotype-gene expression relationships hold over mutliple brain regions and, by comparison with other large datasets in the public domain, other tissue types. However, a small number of correlations appear to be specific to a single brain region and this is not explained by lack of detection in other regions. We are therefore extending these approaches by using laser capture microdissection to isolate defined neuronal populations and repeating the experiments.
| Erskine, Daniel; Ding, Jinhui; Thomas, Alan J et al. (2018) Molecular changes in the absence of severe pathology in the pulvinar in dementia with Lewy bodies. Mov Disord 33:982-991 |
| Chen-Plotkin, Alice S; Albin, Roger; Alcalay, Roy et al. (2018) Finding useful biomarkers for Parkinson's disease. Sci Transl Med 10: |
| Nuriel, Tal; Peng, Katherine Y; Ashok, Archana et al. (2017) The Endosomal-Lysosomal Pathway Is Dysregulated by APOE4 Expression in Vivo. Front Neurosci 11:702 |
| Dillman, Allissa A; Majounie, Elisa; Ding, Jinhui et al. (2017) Transcriptomic profiling of the human brain reveals that altered synaptic gene expression is associated with chronological aging. Sci Rep 7:16890 |
| Civiero, Laura; Cogo, Susanna; Kiekens, Anneleen et al. (2017) PAK6 Phosphorylates 14-3-3? to Regulate Steady State Phosphorylation of LRRK2. Front Mol Neurosci 10:417 |
| Yellajoshyula, Dhananjay; Liang, Chun-Chi; Pappas, Samuel S et al. (2017) The DYT6 Dystonia Protein THAP1 Regulates Myelination within the Oligodendrocyte Lineage. Dev Cell 42:52-67.e4 |
| Hibar, Derrek P (see original citation for additional authors) (2017) Novel genetic loci associated with hippocampal volume. Nat Commun 8:13624 |
| Cookson, Mark R (2017) RNA-binding proteins implicated in neurodegenerative diseases. Wiley Interdiscip Rev RNA 8: |
| Cookson, Mark R (2017) Gene Linkage and Systems Biology. Adv Neurobiol 15:479-489 |
| Soreq, Lilach; UK Brain Expression Consortium; North American Brain Expression Consortium et al. (2017) Major Shifts in Glial Regional Identity Are a Transcriptional Hallmark of Human Brain Aging. Cell Rep 18:557-570 |
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