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To better define the structure and origin of the Bulgarian paternal gene pool, we have examined the Y-chromosome variation in 808 Bulgarian males. The analysis was performed by high-resolution genotyping of biallelic markers and by analyzing the STR variation within the most informative haplogroups. We found that the Y-chromosome gene pool in modern Bulgarians is primarily represented by Western Eurasian haplogroups with ∼ 40% belonging to haplogroups E-V13 and I-M423, and 20% to R-M17. Haplogroups common in the Middle East (J and G) and in South Western Asia (R-L23*) occur at frequencies of 19% and 5%, respectively. Haplogroups C, N and Q, distinctive for Altaic and Central Asian Turkic-speaking populations, occur at the negligible frequency of only 1.5%. Principal Component analyses group Bulgarians with European populations, apart from Central Asian Turkic-speaking groups and South Western Asia populations. Within the country, the genetic variation is structured in Western, Central and Eastern Bulgaria indicating that the Balkan Mountains have been permeable to human movements. The lineage analysis provided the following interesting results: (i) R-L23* is present in Eastern Bulgaria since the post glacial period; (ii) haplogroup E-V13 has a Mesolithic age in Bulgaria from where it expanded after the arrival of farming; (iii) haplogroup J-M241 probably reflects the Neolithic westward expansion of farmers from the earliest sites along the Black Sea. On the whole, in light of the most recent historical studies, which indicate a substantial proto-Bulgarian input to the contemporary Bulgarian people, our data suggest that a common paternal ancestry between the proto-Bulgarians and the Altaic and Central Asian Turkic-speaking populations either did not exist or was negligible. [ABSTRACT FROM AUTHOR]

Using principal component (PC) analysis, we studied the genetic constitution of 3,112 individuals from Europe as portrayed by more than 270,000 single nucleotide polymorphisms (SNPs) genotyped with the Illumina Infinium platform. In cohorts where the sample size was >100, one hundred randomly chosen samples were used for analysis to minimize the sample size effect, resulting in a total of 1,564 samples. This analysis revealed that the genetic structure of the European population correlates closely with geography. The first two PCs highlight the genetic diversity corresponding to the northwest to southeast gradient and position the populations according to their approximate geographic origin. The resulting genetic map forms a triangular structure with a) Finland, b) the Baltic region, Poland and Western Russia, and c) Italy as its vertexes, and with d) Central- and Western Europe in its centre. Inter- and intra- population genetic differences were quantified by the inflation factor lambda (l) (ranging from 1.00 to 4.21), fixation index (Fst) (ranging from 0.000 to 0.023), and by the number of markers exhibiting significant allele frequency differences in pair-wise population comparisons. The estimated lambda was used to assess the real diminishing impact to association statistics when two distinct populations are merged directly in an analysis. When the PC analysis was confined to the 1,019 Estonian individuals (0.1% of the Estonian population), a fine structure emerged that correlated with the geography of individual counties. With at least two cohorts available from several countries, genetic substructures were investigated in Czech, Finnish, German, Estonian and Italian populations. Together with previously published data, our results allow the creation of a comprehensive European genetic map that will greatly facilitate inter-population genetic studies including genome wide association studies (GWAS). [ABSTRACT FROM AUTHOR]

Variation in genetic factors together with xenobiotic exposure may result in increased risk of colorectal cancer. The P-glycoprotein (P-gp) is highly expressed in the apical membrane of enterocytes, where it pumps xenobiotics from the enterocytes back into the intestinal lumen. Thus, polymorphisms that reduce the activity of the MDR1 (ABCB1) efflux pump are potential risk factors for colorectal carcinogenesis. The aim of the present study is to genotype the MDR1 2677G>T (rs2032582) and 3435C>T (rs1045642) polymorphism in patients with colorectal cancer and controls and to identify a possible association between individual genetic variation and susceptibility to colorectal cancer. In the present study, 146 Bulgarian patients with sporadic colorectal cancer and 160 healthy Bulgarian volunteers were evaluated for the two polymorphisms in MDR1. Polymorphisms were identified using rapid-cycle real-time amplification with allele-specific probes and subsequent melting curve analyses on a LightCycler™ (Roche Diagnostics, Mannheim, Germany). No differences were found between the frequencies of the two mutant alleles in the tumor tissue from the cases and lymphocytes from the controls [frequencies of 2677T: 43.5% in patients and 44.1% in controls; frequencies of 3435T: 48.3% in patients and 50.9% in controls (both P > 0.05)]. The MDR1 polymorphic sequence of the tumor tissue always matched that of normal intestinal tissue from the same patient. Consequently, genotyping of DNA from archived tumor tissues is a valid alternative to the use of leukocyte DNA. The present study suggests that MDR1 2677G>T and 3435C>T polymorphism is not a risk factor for sporadic colon cancer among Bulgarians and that somatic mutation at these sites is not involved in the genesis of colon tumors. Further examination using larger number of samples must be necessary to reach to more reliable conclusions. [ABSTRACT FROM AUTHOR]

Background: Several linkage studies suggest that chromosome 5q31-32 might contain risk loci for schizophrenia (SZ). We wanted to identify susceptibility genes for schizophrenia within this region. Methods: We saturated the interval between markers D5S666 and D5S436 with 90 polymorphic microsatellite markers and genotyped two sets of DNA pools consisting of 300 SZ patients of Bulgarian origin and their 600 parents. Positive associations were followed-up with SNP genotyping. Results: Nominally significant evidence for association (p < 0.05) was found for seven markers (D5S0023i, IL9, RH60252, 5Q3133_33, D5S2017, D5S1481, D5S0711i) which were then individually genotyped in the trios. The predicted associations were confirmed for two of the markers: D5S2017, localised in the SPRY4-FGF1 locus (p = 0.004) and IL9, localized within the IL9 gene (p = 0.014). Fine mapping was performed using single nucleotide polymorphisms (SNPs) around D5S2017 and IL9. In each region four SNPs were chosen and individually genotyped in our full sample of 615 SZ trios. Two SNPs showed significant evidence for association: rs7715300 (p = 0.001) and rs6897690 (p = 0.032). Rs7715300 is localised between the TGFBI and SMAD5 genes and rs6897690 is within the SPRY4 gene. Conclusion: Our screening of 5q31-32 implicates three potential candidate genes for SZ: SMAD5, TGFBI and SPRY4. [ABSTRACT FROM AUTHOR]

Abstract: Objectives:: The concept of multifactorial etiology of BEN anticipates that a combination of polymorphic gene variants and various environmental factors causes an increased risk for the disease. CYP enzymes play a key role in the metabolic activation of environmental chemicals and toxins. CYP3A enzymes are particularly relevant for xenobiotic metabolism because of their broad substrate specificity and abundant expression in the human liver, intestine, and kidney. Previous phenotyping analysis on CYP2D6 enzyme activity in BEN patients proposed a modifying effect of CYP2D6 gene variants on BEN risk, but it was not approved with molecular–genetic methods. The aim of the current case-control study was to compare the frequency of CYP2D6 and CYP3A5 polymorphisms, as well as one CYP3A4 promoter variant in BEN patients and controls in order to investigate a possible association between individual genetic variations in these genes and susceptibility to BEN. Design and methods:: Ninety-six nonrelated Bulgarian BEN patients from endemic villages in the Vratza district and 112 healthy Bulgarians from nonendemic areas (controls) were genotyped. Identification of alleles was done by allele-specific PCR or by rapid-cycle amplification on the LightCycler, followed by sequence-specific detection. Results:: The UM, PM, and EM + IM genotype frequencies of CYP2D6 did not differ significantly between the two groups (P > 0.05). The CYP3A4*1B allele was only found in the heterozygous form, with allelic frequencies of 5.21% in the patients and 2.23% in the healthy individuals (P = 0.11). The CYP3A5*1 allele was more prevalent in BEN patients with a frequency of 9.38% compared to 5.36% in the controls and was associated with a higher risk for BEN (OR 2.41, 95% CI 1.09–5.33) (P = 0.02). Conclusions:: Our results demonstrate that the CYP3A5*1 allele, previously reported as a marker for CYP3A5 expression in human kidney, is associated with increased risk for BEN, while CYP3A4*1B and CYP2D6 genotypes do not significantly modify the risk for the disease. [Copyright &y& Elsevier]

Abstract: Background: Bipolar affective disorder (BAD) is a psychiatric illness characterized by episodes of mania and depression. Although the etiology is not clear, epidemiological studies suggest it is a result of an interaction of genetic and environmental factors. Despite of enormous efforts and abundant studies conducted, none has yet been identified definitively a gene susceptible to bipolar disorder. Methods: Ninety-four Bulgarian patients diagnosed with bipolar disorder and 184 Bulgarian healthy individuals, were used for genotyping of 191 single nucleotide polymorphisms (SNPs) by TaqMan and/or Invader assays. Seventeen SNPs that revealed P value less than 0.05 in the first screening were genotyped using an additional independent set of samples, consisting of 78 BAD cases and 372 controls. Results: After applying the Bonferonni correction on genotyping results of 172 cases and 556 controls, only one SNP, rs1800883, in the HTR5A gene revealed a significant level of P value (P =0.000097; odds ratio=1.80 (95%CI, 1.27–2.54); corrected P =0.017). Conclusions: Our findings suggest that HTR5A gene could play an important role in the pathogenesis of bipolar disorder in our population. However these findings should be viewed with caution and replication studies in other populations are necessary in support of these findings. [Copyright &y& Elsevier]

: BackgroundThe gene encoding the dystrobrevin binding protein (DTNBP1) has been implicated in the pathogenesis of schizophrenia by several association studies. We tried to replicate these findings in a sample of 488 parent–proband trios recruited in Bulgaria. Probands had a diagnosis of schizophrenia (n = 441) or schizoaffective disorder (n = 47).: MethodsWe genotyped eight single nucleotide polymorphisms within the gene, four of which had been reported in previous studies, and four identified as informative by our group through direct screening of the gene and genotyping in a sample of cases and control subjects.: ResultsA significant excess of transmissions was observed for two of the markers, p1635 and p1757, (p = .0009 and .0013, respectively). Analysis of two-, three-, and four-marker haplotypes produced numerous positive results, with six (4% of the total combinations) at p < .001.: ConclusionsThese results provide strong support for DTNBP1 as a susceptibility gene for schizophrenia; however, different haplotypes seem to be associated in different studies. [Copyright &y& Elsevier]

We screened for variation in the 12 protocadherin γ A (PCDHGA) genes of the protocadherin cluster on chromosome 5q31. We used denaturing high-performance liquid chromatography followed by sequencing to identify changes in the DNA sequence. We identified 24 nonsynonymous changes, 24 synonymous SNPs, and 9 polymorphisms in the 5′ flanking regions. The variant with the greatest predicted impact on the encoded protein was a frameshift polymorphism in PCDHGA8, caused by a deletion of one C base (Pro174fsdelC). The del variant was more common in 512 controls compared to 506 schizophrenic (SZ) cases (10.6% vs 7.2%, p = 0.007) but this trend was not replicated in an independent sample of 403 trios, in which it was transmitted 47 times and not transmitted 55 times from heterozygous parents (p = 0.43). We screened 10 of the common polymorphisms for association with schizophrenia by genotyping pooled DNA from 540 SZ cases and 540 controls, but none of them showed a significant difference. It will be important to identify the phenotype associated with the loss of the PCDHGA8 gene. [Copyright &y& Elsevier]