Whether heterozygous carriers of PARK2 mutations are at increased risk of PD has been a controversial topic in recent years. Here is some evidence that heterozygous CNV carriers (note not mutations) may be at elevated risk of Parkinson's...
Hum Mol Genet. 2015 Jul 17. pii: ddv277. [Epub ahead of print]
Huttenlocher J, Stefansson H, Steinberg S, Helgadottir HT, Sveinbjörnsdóttir S, Riess O, Bauer P, Bauer P.
Together with point mutations, homozygous deletions or duplications in PARK2 are responsible for the majority of autosomal recessive juvenile Parkinsonism. It is debated, however, whether heterozygous carriers of these mutations are at increased risk of Parkinson's disease (PD).Our goal was to determine whether heterozygous carriers of copy number variants (CNVs) affecting exons of the PARK2 gene are at risk of PD that is greater than that of non-carriers.We searched for CNVs affecting exons of PARK2 in a sample of 105,749 genotyped Icelanders. In total 989 carriers, including 24 diagnosed with PD, were identified. The heterozygous carriers were tested for association in a sample of 1,415 PD patients and 40,474 controls≥65 years of age. PD patients were more often heterozygous carriers of PARK2 CNVs than controls (OR=1.69, P=0.03) and compound heterozygous PD patients for a CNV and a missense mutation were not found. Furthermore we conducted a meta-analysis of studies reporting on case-control samples screened for heterozygous PARK2 CNVs. Ten studies were included in the final analysis, with 4,538 cases and 4,213 controls. The pooled OR and P-value for the published and Icelandic results showed significant association between PARK2 CNVs and risk of PD (OR=2.11, P=2.54 x 10-6).Our analysis shows that heterozygous carriers of CNVs affecting exons of PARK2 have greater risk of PD than non-carriers.
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