1) We developed a haplotype-based approach (HAP-PDT) to analyze rare variants within pedigrees with complex human disorders. Extensive simulations in the sequencing setting were carried out to evaluate and compare the haplotype-based approach with the rare variant methods that drew on a more conventional collapsing strategy. The haplotype-based pedigree tests had enhanced statistical power compared with the rare variants based pedigree tests when the disease of interest was mainly caused by rare haplotypes (with multiple rare alleles), and vice versa when the disease was caused by rare variants acting independently. The related software was submitted to the Comprehensive R Archive Network (CRAN) for general use as a computer program named rvHAP-PDT. The code has been modified so that it can accommodate more complex pedigree structure in the sequencing era. 2) We also developed a pathway-based pipeline which can be used to link genome-wide association study (GWAS) signals to important biological pathways. We used this pipeline to analyze drug response on OCD (obsessive-compulsive disorder) GWAS data to select significant pathways. We reported the suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). The results presented may provide new insights into genetic mechanisms underlying treatment response in OCD. However, the sample size was limited. We will seek further collaborations to validate the current results using a larger sample size and data sets from different populations.
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