Schizophrenia (SZ) is a multifactorial phenotype. Candidate gene approach and positional cloning are the primary methods for elucidating its etiology.
We genotyped two TNF gene SNPs (-G308A, -G238A) and analyzed the haplotype structure in 24 Canadian families. Our results demonstrate that there is evidence for association (P=0.026) of a specific haplotype with SZ with a Trimhap test. Stratifying the 22 families with genome scan data by TNF promoter haplotypes followed by reanalysis of linkage to SZ, we identified few loci that exhibit a considerable increase in LOD/HLOD scores. A locus on chromosome 1q44 demonstrated a significant increase in LOD from 0.15 to 3.01.
The synapsin 2 (Syn2) gene is implicated in synaptogenesis, neurotransmitter release, and the localization of nitric oxide synthase. 37 pedigrees of Northern European ancestry from the NIMH HGI collection were used in this study. Four microsatellites and twenty SNPs were genotyped. Linkage (FASTLINK) and association (TRANSMIT, PDTPHASE) were evaluated. A maximum HLOD of 1.93 was observed at D3S3434. Significant results were obtained for association with SZ using TRANSMIT (p=0.0000005) and PDTPHASE (p=0.014) using single marker analyses. Haplotype analysis provided a single haplotype that is significantly associated with SZ using TRANSMIT ([less than] 0.00000001) and PDTPHASE (p=0.02).
The results of a linkage scan for SZ in the NIMH HGI Chinese family collection were reported by Faraone et al. with the largest NPL z score of 2.88 for D10S2327. We have reanalyzed the genome using the posterior probability of linkage (PPL). We split the sample into two subsets: those without any family members with affective diagnoses (SZ subgroup); and those with SZ, schizoaffective disorder, and bipolar disorder (HET subgroup). Genotypes were cleaned using PEDCHECK and SIMWALK. Sample specific genetic maps were constructed. SZ and HET groups were analyzed by four-point PPL analysis, and the results from each group were combined via pooling and sequential updating. The results confirmed the linkage peak on 10q22 with a PPL of 32.1% after updating. In addition we observed a peak of 30.5% over D3S1311 on 3q29 coming primarily from the HET group. Our results confirmed previous and yielded novel linkage findings in this family sample.Ph.D.Includes bibliographical references (p. 111-125)
