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Parkinson’s disease (PD) is characterized by cerebral dopamine depletion that causes motor and cognitive deficits. The dopamine-related gene  ANKK1  has been associated with neuropsychiatric disorders with a dopaminergic deficiency in the striatum. This study aims to define the contribution of  ANKK1  rare variants in PD. We found in 10 out of 535 PD patients 6  ANKK1  heterozygous rare alleles located at the 5′UTR, the first exon, intron 1, and the nearby enhancer located 2.6 kb upstream. All 6  ANKK1  single nucleotide variants were located in conserved regulatory regions and showed significant allele-dependent effects on gene regulation in vitro . ANKK1  variant carriers did not show other PD-causing Mendelian mutations. Nevertheless, four patients were heterozygous carriers of rare variants of  ATP7B  gene, which is related to catecholamines. We also found an association between the polymorphic rs7107223 of the  ANKK1  enhancer and PD in two independent clinical series ( P  = 0.007 and 0.021). rs7107223 functional analysis showed significant allele-dependent effects on both gene regulation and dopaminergic response. In conclusion, we have identified in PD patients functional variants at the  ANKK1  locus highlighting the possible relevance of rare variants and non-coding regulatory regions in both the genetics of PD and the dopaminergic vulnerability of this disease.

Regulatory rare variants of the dopaminergic gene ANKK1 as potential risk factors for Parkinson’s disease