Summary: Emerging evidence indicates that the DRD1‐BDNF‐DRD3 cluster plays an important role in nicotine addiction. We have performed an association analysis of 42 SNPs within these genes with cigarette consumption in a group of 341 schizophrenia patients. The ACCG haplotype consisting of four BDNF markers (Val66Met (rs6265), rs11030104, rs2049045 and rs7103411) showed an association with the risk of smoking (p = 0.0002). Both DRD1 markers tested (rs4532 and rs686) and the DRD3 marker (rs1025398) showed association with quantity of tobacco smoked (p = 0.01, 0.005 and 0.002, respectively). Our findings are preliminary; however, they support the involvement of the DRD1, BDNF and DRD3 genes in smoking behaviour.

Whole genome scan studies have recently identified the NRXN1 and NRXN3 genes as potential contributing factors in the risk for nicotine addiction. We have genotyped 15 single nucleotide polymorphisms (SNPs) spanning the NRXN1 and NRXN3 genes in 195 unrelated patients with schizophrenia for whom information about their smoking status and number of cigarettes smoked per day (CPD) was obtained. The NRXN3 marker rs1004212 was significantly associated with quantity of tobacco smoked. Individuals homozygous for the C allele of rs1004212 smoked more cigarettes per day than heterozygous individuals. We found no significant association of markers within the NRXN1 gene with the risk of smoking or the quantity of tobacco smoked. Because of the relatively small sample size, this is a preliminary study. However, this candidate gene study supports the observations of molecular studies implicating the NRXN genes in drug addiction and suggests that variants in the NRXN3 gene could contribute to the degree of nicotine dependence in patients with schizophrenia.

Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disorder, characterized by the loss of dopaminergic neurons (mDA) in the midbrain. The underlying mechanisms are only partly understood and there is no treatment to reverse PD progression. Here, we investigated the disease mechanism using mDA neurons differentiated from human induced pluripotent stem cells (hiPSCs) carrying the ILE368ASN mutation within the PINK1 gene, which is strongly associated with PD. Single-cell RNA sequencing (RNAseq) and gene expression analysis of a PINK1-ILE368ASN and a control cell line identified genes differentially expressed during mDA neuron differentiation. Network analysis revealed that these genes form a core network, members of which interact with all known 19 protein-coding Parkinson’s disease-associated genes. This core network encompasses key PD-associated pathways, including ubiquitination, mitochondrial function, protein processing, RNA metabolism, and vesicular transport. Proteomics analysis showed a consistent alteration in proteins of dopamine metabolism, indicating a defect of dopaminergic metabolism in PINK1-ILE368ASN neurons. Our findings suggest the existence of a network onto which pathways associated with PD pathology converge, and offers an inclusive interpretation of the phenotypic heterogeneity of PD.