The transcription factor Nrf2, encoded by the NFE2L2 gene, is an important regulator of the cellular protection against oxidative stress. Parkinson’s disease is a neurodegenerative disease highly associated with oxidative stress. In a previously published study, we reported associations of NFE2L2 haplotypes with risk and age at onset of idiopathic Parkinson’s disease in a Swedish discovery material and a Polish replication material. Here, we have extended the replication study and performed meta-analyses including the Polish material and four new independent European patient-control materials. Furthermore, all SNPs included in the haplotype windows were investigated individually for associations with Parkinson’s disease in meta-analyses including all six materials. Totally 1038 patients and 1600 control subjects were studied. Based on previous NFE2L2 haplotype associations with Parkinson’s disease, five NFE2L2 tag SNPs were genotyped by allelic discrimination and three functional NFE2L2 promoter SNPs were genotyped by sequencing. The impact of individual SNPs and haplotypes on risk and age at onset of Parkinson’s disease were investigated in each material individually and in meta-analyses of the obtained results. Meta-analyses of NFE2L2 haplotypes showed association of haplotype GAGCAAAA, including the fully functional promoter haplotype AGC, with decreased risk (OR = 0.8 per allele, p = 0.012) and delayed onset (+1.1 years per allele, p = 0.048) of Parkinson’s disease. These results support the previously observed protective effect of this haplotype in the first study. Further, meta-analyses of the SNPs included in the haplotypes revealed four NFE2L2 SNPs associated with age at onset of Parkinson’s disease (rs7557529 G > A, −1.0 years per allele, p = 0.042; rs35652124 A > G, −1.1 years per allele, p = 0.045; rs2886161 A > G, −1.2 years per allele, p = 0.021; rs1806649 G > A, +1.2 years per allele, p = 0.029). One of these (rs35652124) is a functional SNP located in the NFE2L2 promoter. No individual SNP was associated with risk of Parkinson’s disease. Our results support the hypothesis that variation in the NFE2L2 gene, encoding a central protein in the cellular protection against oxidative stress, may contribute to the pathogenesis of Parkinson’s disease. Functional studies are now needed to explore these results further.

Background: Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disorder characterized by abnormal tau protein aggregation. The MAPT gene encodes for tau protein. The MAPT locus harbors two major haplotypes, H1 and H2, with H1 and its subhaplotypes being associated with an increased risk of PSP. Methods: In this study, we genotyped rs8070723 in a cohort of 73 PSP patients, including 47 PSP Richardson Syndrome (PSP-RS) and 27 PSP variants (vPSP), and 93 age-matched healthy controls (HC) from Southern Italy. Results: Haplotype analysis identified H1 and H2 haplotypes that conferred a risk (OR, 2.620; 95% CI, 1.399–5.140; p = 0.0035) and a protective effect (OR, 0.370; 95% CI, 0.196–0.695; p = 0.0015), respectively. In addition, we genotyped five MAPT variants (rs1467967, rs242557, rs3785883, rs2471738, and rs7521) that, together with rs8070723, defined H1 subhaplotypes. We identified 18 distinct MAPT H1 subhaplotypes, among which H1j displayed a nominally significant reduced risk of PSP (OR, 0.201; 95% CI, 0.044–0.915; p = 0.0265). Conclusions: These findings reinforce the role of MAPT genetic variation in PSP pathogenesis and highlight the potential impact of haplotype diversity on disease susceptibility.

Pathogenic KCNQ2 variants are associated with neonatal epilepsies, ranging from self-limited neonatal epilepsy to KCNQ2–developmental and epileptic encephalopathy (DEE). In this study, next-generation sequencing was performed, applying a panel of 142 epilepsy genes on three unrelated individuals and affected family members, showing a wide variability in the epileptic spectrum. The genetic analysis revealed two likely pathogenic missense variants (c.1378G>A and c.2251T>G) and the already-reported pathogenic splice site (c.1631+1G>A) in KCNQ2 (HGNC:6296). The phenotypes observed in the affected members of family 1, which shared the c.2251T>G variant, were epilepsy with auditory features (EAFs), focal epilepsy, and generalized epilepsy, and none of them suffered from neonatal seizures. The gene panel contained further genes related to EAFs (LGI1, RELN, SCN1A, and DEPDC5), which were tested with negative results. The phenotypes observed in family 2 members, sharing the splice site variant, were neonatal seizures and focal epilepsy in childhood. The last unrelated proband, harboring the de novo missense c.1378G>A, presented a clinical phenotype consistent with DEE. In conclusion, we identified two unreported KCNQ2 variants, and report a proband with EAFs and individuals without typical KCNQ2 neonatal seizures. Our study underscores the extreme variability in the phenotypic spectrum of KCNQ2-related epilepsies and unveils the prospect of its inclusion in screening panels for EAFs.