Objective: To evaluate gene-environment interactions between head injury and candidate single nucleotide polymorphisms (SNP) in Parkinson’s disease (PD).

Background: Head injury is consistently associated with development of PD in epidemiological studies. However, the biological mechanism through which head injury increases PD risk remains unclear. Disentangling gene-environment interactions (GxE) between candidate SNPs and head injury in a quantitative manner may uncover putative, modifiable, causal mechanisms.

Method: This study utilised Tier 2 data from the Global Parkinson’s Genetics Program (GP2). The cohort was restricted to European ancestry individuals only, leaving a cohort of 2,305 individuals with both head injury data, and genetic data (n(PD)=993, n(control)=1,312). Candidate SNPs for GxE analysis were selected through: 1) literature review; 2) hypothesis-driven analyses testing if having head trauma was associated with SNP allele dosage, via logistic regression (i.e., ‘Head Trauma’ ~ SNP + covariates; all SNPs tested (GWAS)). This generated six candidate SNPs for formal analysis. Formal GxE logistic regression models then tested the interaction between head injury and SNPs in cases and controls with PD status as the outcome. Models were adjusted for age, sex, and the first five principal components.

Results: Two variants were significant at an FDR-corrected p(interaction) value in GxE testing. chr3:151405709:T:C was a risk variant (p(interaction)=0.037, OR (CI) per effect allele in head trauma 1.90 (1.16-3.12)). By contrast, chr4:138873712:GT:G was protective (p(interaction)=0.037, OR (CI) per effect allele in head trauma 0.53 (0.31-0.91)).

Conclusion: chr3:151405709:T:C is a known risk variant for PD, near MED12L. MED12L encodes a subunit of the mediatory transcriptional regulatory complex, and we suggest there is a plausible mechanism through which head injury and chr3:151405709:T:C interact to increase pathological neuroinflammation driving PD risk. chr4:138873712:GT:G is a novel variant, without known biological function at present, that requires further exploration. Future work will 1) further interrogate the relationship between chr3:151405709:T:C and head injury at a biological level, and 2) use larger cohorts to identify further SNPs that may interact with head injury.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/evaluating-gene-environment-interactions-between-head-injury-and-parkinsons-disease-risk-variants/