Is the MC1R variant p.R160W associated with Parkinson’s?

MC1R variants are known to be involved with pigmentation phenotypes and malignant melanoma (MM), with p.R160W associated with red hair and fair skin, as well as increased MM risk¹. Tell-Marti et al. recently reported in the Annals of Neurology, that p.R160W conferred an increased risk for Parkinson’s (PD)². However, a meta-analyses including International Parkinson’s Disease Genomics Consortium (IPDGC) data previously failed to observe any association³. We therefore re-investigated p.R160W in an additional large cohort collected through the IPDGC, using high-quality genotype data obtained from the NeuroX chip.

Based on Tell-Marti’s observed control minor allele frequency (MAF), our cohort of 5,944 PD cases and 4,642 controls had 99.3% power to detect a 2.1-fold increased risk (compared to their 32.6% power). Our analysis, using logistic regression (correcting for gender and population structure), did not identify a significant association between p.R160W and PD (OR=1.01, 0.90–1.13) (Table 1). Overall MC1R variants can vary greatly between European populations, with higher variant frequencies in fairer Northern European Caucasian populations. Conversely, Mediterranean populations have lower variant frequencies⁴. Different proportions of Mediterranean Caucasian ancestry could contribute to allelic heterogeneity. No evidence of allelic heterogeneity between the different subsets existed in our data (I²=0%, P_het=0.545). The MAF for p.R160W in the Greek and French subsets were comparable to Tell-Marti’s report and other Mediterranean Caucasian populations^4,5. No association with PD was seen in these southern European subsets (Greek, OR=1.34, 0.92–1.95; French, OR=1.00, 0.61–1.66), nor within any other subset (Table 1).

Table 1.

No association of the MC1R variant p.R160W and Parkinson’s in a large heterogeneous cohort.

	OR (95% CI)	P-value	Controls		Cases
			MAF	N	MAF	N
NeuroX Genotyped samples#	1.01 (0.90–1.13)	0.853	0.062	4,642	0.064	5,944
Dutch	0.86 (0.57–1.30)	0.469	0.075	409	0.066	312
French	1.00 (0.61–1.66)	0.989	0.040	451	0.036	508
German	1.10 (0.87–1.41)	0.425	0.068	880	0.075	1,296
Greek	1.34 (0.92–1.95)	0.131	0.026	882	0.034	965
UK	0.95 (0.72–1.24)	0.624	0.080	583	0.073	1,107
US	0.92 (0.76–1.12)	0.385	0.077	1,437	0.074	1,756
Tell-Marti et al.@	2.10 (1.18–3.73)	0.009	0.010	736	0.025	870
Dong et al.+	0.98 (0.89–1.07)	0.624	-	13,642	-	6,141

KEY:

^#logistic regression correcting for gender and population stratification.

^@logistic regression correcting for gender and age.

⁺meta-analysis of 5,333 cases and 12,019 controls from the International Parkinson’s Disease Genomics Consortium; and 808 cases and 1,623 controls from the Parkinson’s Genes and Environment Study.

CI, confidence interval; MAF, minor allele frequency; N, number of samples; OR, odds ratio; UK, United Kingdom; US, United States.

A potential limitation of Tell-Marti’s study is their selection of controls which were predominantly collected from the wider Spanish population with cases selected from Barcelona. Although the Spanish population is largely homogenous, patterns of genetic microstructure distinguish people from different regions within Spain. This genetic substructure could therefore be a potential source of bias⁶. Additionally, excluding dermatology and oncology patients as controls could have inadvertently lowered p.R160W incidence and may have inflated their effect size.

A shared genetic background between PD and MM has been suggested, but based on our analysis of >11,000 individuals from various different population groups and that reported by Dong et al.³, we can conclude that the p.R160W variant and other common variants are not associated with PD.