Genome-Wide Supported Risk Variants in MIR137, CACNA1C, CSMD1, DRD2, and GRM3 Contribute to Schizophrenia Susceptibility in Pakistani Population

OBJECTIVE: Schizophrenia is a chronic neuropsychiatric disease afflicting around 1.1% of the population worldwide. Recently, MIR137, CACNA1C, CSMD1, DRD2, and GRM3 have been reported as the most robustly emerging candidates involved in the etiology of schizophrenia. In this case control study, we performed an association analysis of rs1625579 (MIR137), rs1006737, rs4765905 (CACNA1C), rs10503253 (CSMD1), rs1076560 (DRD2), rs12704290, rs6465084, and rs148754219 (GRM3) in Pakistani population. METHODS: Schizophrenia was diagnosed on the basis of the Diagnostic and Statistical Manual of Mental Disorders 4th ed (DSM-IV). Detailed clinical information, family history of all patients and healthy controls were collected. RFLP based case control association study was performed in a Pakistani cohort of 508 schizophrenia patients and 300 healthy control subjects. Alleles and genotype frequencies were calculated using SPSS. RESULTS: A significant difference in the genotype and allele frequencies for rs4765905, rs1076560 and rs6465084 were found between the patients and controls (p=0.000). CONCLUSION: This study provides substantial evidence supporting the role of CACNA1C, GRM3 and DRD2 as schizophrenia susceptibility genes in Pakistani population.

Report of a recurrent mutation in ARS [component B] gene with severe Mal de Meleda in a large consanguineous Pakistani family

To characterize the disease causing mutation in a large consanguineous Pakistani family with severe Mal de Meleda [MDM] or keratosis palmoplantaris transgrediens, a rare autosomal recessive skin disorder. Single nucleotide polymorphism [SNPs] genotyping was performed using the GeneChip Mapping 250K array [Affymetrix]. Homozygosity mapping and sorting of genomic regions were performed with dedicated software called AutoSNPa. Selected regions were further investigated by genotyping with microsatellite markers derived from known and novel polymorphic repeats. Two-point LOD score calculation was performed by using the MLINK of Fastlink computer package. All three coding exons of ARS [component B] gene were amplified by PCR and sequenced. Sequencing of all the coding exons of ARS [component B] gene in the affected individuals revealed a recurrent missense mutation in exon 3 at base pair 256 from Guanine to Alanine [256G>A] and as a result the amino acid Glycine is replaced by Arginine at position 86 [G86R]. This finding will facilitate control of affected MDM births in the Pakistani families