Balkan Journal of Medical Genetics

RTN4 AND FBXL17 GENES ARE ASSOCIATED WITH CORONARY HEART DISEASE IN GENOME-WIDE ASSOCIATION ANALYSIS OF LITHUANIAN FAMILIES
Domarkienė I1,*, Pranculis A1, Germanas Š1, Jakaitienė A1, Vitkus D2, Dženkevičiūtė V3, Kučinskienė ZA2, Kučinskas V1
*Corresponding Author: Ingrida Domarkienė, Department of Human and Medical Genetics, Faculty of Medicine, Vilnius University, Santariškių str. 2, 08661 Vilnius, Lithuania; Tel.: +370-52501788; E-mail: ingrida.domarkiene@ mf.vu.lt
page: 17

RESULTS

According to the Illumina Inc. protocol guidelines, all of the samples except one, were of good quality and had been properly processed (call rate >98; LogRDev <0.3; coincidental sex list file created). At the beginning of the analysis there were 731,412 SNPs genotyped in the group of 96 individuals. After the data filtering procedure, two individuals were removed from further analysis for low genotyping (MIND >0.05); 25,293 heterozygous genotypes were excluded from analysis because the second allele of the genotype was missing; 298 SNPs were excluded based on the Hardy-Weinberg equilibrium test (p >0.0005); 2528 SNPs failed missingness test (GENO >0.1); 82,552 SNPs failed frequency test (MAF <0.01); 591 SNP were not used because of homogeneity over all individuals. After the final frequency and genotyping pruning, 646,445 SNPs in 31 patient and 63 parents were included for further association analysis. Twelve SNPs were found to be significantly associated with CHD phenotype with p values smaller than 0.0001. The SNPs annotation (transmitted allele, chromosomal position, gene, gene function) along with the c2, p value, OR and empirical power based on the sample size calculations, are presented in Table 1. The SNPs are annotated according to the National Center for Biotechnology Information (NCBI) dbSNP and Gene databases [9]. The acceptable power values were greater than or equal to 0.65, and thus fell partly into the desired range between 0.8 and 0.95 [10]. Only the power value of the significant SNP rs1321936 diverged and was excluded from further evaluation. The OR values in Table 1 show the size of the effect. The greater the deviation of OR is from the value of 1, the more significant the test is. As can be seen from the Manhattan plot (Figure 1), there are three significant markers (rs12734338, rs3883013, rs3853444) that do not have the significant adjacent SNPs (according to the nucleotide’s position), i.e., the correlation is absent. Thus, these markers could be artefacts. We could also suspect that not all of the adjacent SNPs were genotyped. This is more likely to happen with rs3853444, as there were two adjacent SNPs that were excluded from the analysis. It was previously mentioned that the study group included only male patients and their parents. A male could possess the SNP allele on either his X or Y chromosome and this affects the analysis algorithm. Each transmission from a heterozygous mother to a male offspring should be given twice the weight of a transmission to a female offspring [11]. Thus, the standard TDT appears to be unsuitable for the analysis of SNPs in sex chromosomes and eventually sex chromosomes were excluded from the analysis.

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