Low-frequency and rare coding variants of NUS1 contribute to susceptibility and phenotype of Parkinson's disease

•For the first time, identify the association between rs539668656 and PD risk.•NUS1 rare variants, or rs539668656 was associated with PD phenotype.•Rs969919569, c.432T>G and rs369403261 were predicted to be deleterious. NUS1 has been recently identified as a candidate gene for Parkinson's disease (PD). Few studies have examined the association of NUS1 variants with PD susceptibility and phenotypes. In the first cohort, whole-exome sequencing was performed to identify variants in NUS1 exon-coding and exon-intron regions in 1542 cases and 1625 controls. 13 variants were totally detected, of which 10 rare variants and 3 low-frequency variants. Burden analysis showed that rare NUS1 variants significantly enriched in PD (p=0.016). We also performed a meta-analysis based on previous and our studies to correlate NUS1 mutations with PD susceptibility. Integrating our previous cohort (3210 cases and 2807 controls) and the first cohort identified the significant association of rs539668656 with PD risk (odds ratio (OR) = 2.82, p = 0.016). The genotype-phenotype association analysis showed that patients carrying rare variants, or rs539668656 were significantly associated with earlier onset age, depression, emotional impairment and severe disease condition. Our results support the role of NUS1 rare variants and rs539668656 towards PD susceptibility and phenotype.