A Systematic Study of Schizophrenia Susceptibility Loci
Shi YongYong
ABSTRACT
Schizophrenia is a severe mental disorder that affects approximately 1% of the population with lifelong devastating consequences. Decades of extensive efforts have been dedicated to the search of DNA sequence variations that increase the risk to schizophrenia. However, the mode of transmission is complex and non-Mendelian. Unknown environmental effects and diagnostic ambiguities of the disease have made genetic studies in schizophrenia quite unproductive.
First, based on the theory of studying complex disease, the author develops two powerful statistical analysis tools. One is SHEsis, focusing on traditional association tests for main effects; the other is PDSE, a new algorithm for Purely Detecting Susceptibility Epistasis and can be used in huge scale gene mapping. SHEsis makes it convenient to get almost all the useful statistical parameters of association study. PDSE studies susceptibility gene-interactions/epistasis which is seldomly analyzed in the past.
Second, case-control samples are collected from Shanghai and Jilin province for association study. Before analyzing schizophrenia susceptibility, the author studies the genetic background of those Han Chinese samples. The results show that stratification exists in the sample set, but its distribution will never cause spurious positive results. And, some Yao and BouYei samples are also collected for a simple analysis on the genetic background of Chinese populations.
Third, 10 genes are chosen for gene-based association studies(for main effects), including SLIT3(65 SNPs)，DTNBP1(7 SNPs)，CAPON(4 SNPs)，TNFB(4 SNPs)，DBH(3 SNPs)，DRD3(1 SNP)，DISC1(4 SNPs)，COMT(2 SNPs)，PIK4CA(1 SNP)，and ZDHHC8(1 SNP). ZDHHC8 shows a strong significance in samples from Shanghai, while no deviation in Jilin samples. The significant result confirms the report of Chen WY et al. And the heterogeneity can be the reason of contradictory reports on this gene. 2 SNPs, rs9476837 and rs9464794 in DTNBP1 show great significances and 3-SNP haplotype rs11755055-rs9476837-rs9464794 is significant too. But the frequencies of all 3 SNPs are low, and odds ratios are around 1.4~1.6, we need more samples to confirm this result, considering multiple tests correction.
Finally, the author uses PDSE to analyze the susceptibility gene-gene interactions/epistasis. DTNBP1 surprises me again, as pair of rs11755055 and rs9464794 is extremely significant (p=5.87e-15) in susceptibility epistasis analysis. Before getting any explanation, the result needs to be confirmed by analyzing more samples.
In summary, this work is a systematic analysis on schizophrenia susceptibility genes and a series of valuable results have been gained, though the experimental scale is limited.
Key words: schizophrenia, association study, susceptibility epistasis, SHEsis, PDSE, genetic background, DTNBP1, ZDHHC8
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