A genome-wide association scan of RR and QT interval duration in 3 European genetically isolated populations:the EUROSPAN project

We set out to identify common genetic determinants of the length of the RR and QT intervals in 2325 individuals from isolated European populations.We analyzed the heart rate at rest, measured as the RR interval, and the length of the corrected QT interval for association with 318 237 single-nucleotide polymorphisms. The RR interval was associated with common variants within GPR133, a G-protein-coupled receptor (rs885389, P=3.9 x 10(-8)). The QT interval was associated with the earlier reported NOS1AP gene (rs2880058, P=2.00 x 10(-10)) and with a region on chromosome 13 (rs2478333, P=4.34 x 10(-8)), which is 100 kb from the closest known transcript LOC730174 and has previously not been associated with the length of the QT interval.Our results suggested an association between the RR interval and GPR133 and confirmed an association between the QT interval and NOS1AP

Genetic Determinants of Circulating Sphingolipid Concentrations in European Populations

Sphingolipids have essential roles as structural components of cell membranes and in cell signalling, and disruption of their metabolism causes several diseases, with diverse neurological, psychiatric, and metabolic consequences. Increasingly, variants within a few of the genes that encode enzymes involved in sphingolipid metabolism are being associated with complex disease phenotypes. Direct experimental evidence supports a role of specific sphingolipid species in several common complex chronic disease processes including atherosclerotic plaque formation, myocardial infarction (MI), cardiomyopathy, pancreatic beta-cell failure, insulin resistance, and type 2 diabetes mellitus. Therefore, sphingolipids represent novel and important intermediate phenotypes for genetic analysis, yet little is known about the major genetic variants that influence their circulating levels in the general population. We performed a genome-wide association study (GWAS) between 318,237 single-nucleotide polymorphisms (SNPs) and levels of circulating sphingomyelin (SM), dihydrosphingomyelin (Dih-SM), ceramide (Cer), and glucosylceramide (GluCer) single lipid species (33 traits); and 43 matched metabolite ratios measured in 4,400 subjects from five diverse European populations. Associated variants (32) in five genomic regions were identified with genome-wide significant corrected p-values ranging down to 9.08 x 10(-66). The strongest associations were observed in or near 7 genes functionally involved in ceramide biosynthesis and trafficking: SPTLC3, LASS4, SGPP1, ATP10D, and FADS1-3. Variants in 3 loci (ATP10D, FADS3, and SPTLC3) associate with MI in a series of three German MI studies. An additional 70 variants across 23 candidate genes involved in sphingolipid-metabolizing pathways also demonstrate association (p = 10(-4) or less). Circulating concentrations of several key components in sphingolipid metabolism are thus under strong genetic control, and variants in these loci can be tested for a role in the development of common cardiovascular, metabolic, neurological, and psychiatric diseases

The genetic study of three population microisolates in South Tyrol (MICROS): study design and epidemiological perspectives

<p>Abstract</p> <p>Background</p> <p>There is increasing evidence of the important role that small, isolated populations could play in finding genes involved in the etiology of diseases. For historical and political reasons, South Tyrol, the northern most Italian region, includes several villages of small dimensions which remained isolated over the centuries.</p> <p>Methods</p> <p>The MICROS study is a population-based survey on three small, isolated villages, characterized by: old settlement; small number of founders; high endogamy rates; slow/null population expansion. During the stage-1 (2002/03) genealogical data, screening questionnaires, clinical measurements, blood and urine samples, and DNA were collected for 1175 adult volunteers. Stage-2, concerning trait diagnoses, linkage analysis and association studies, is ongoing. The selection of the traits is being driven by expert clinicians. Preliminary, descriptive statistics were obtained. Power simulations for finding linkage on a quantitative trait locus (QTL) were undertaken.</p> <p>Results</p> <p>Starting from participants, genealogies were reconstructed for 50,037 subjects, going back to the early 1600s. Within the last five generations, subjects were clustered in one pedigree of 7049 subjects plus 178 smaller pedigrees (3 to 85 subjects each). A significant probability of familial clustering was assessed for many traits, especially among the cardiovascular, neurological and respiratory traits. Simulations showed that the MICROS pedigree has a substantial power to detect a LOD score ≥ 3 when the QTL specific heritability is ≥ 20%.</p> <p>Conclusion</p> <p>The MICROS study is an extensive, ongoing, two-stage survey aimed at characterizing the genetic epidemiology of Mendelian and complex diseases. Our approach, involving different scientific disciplines, is an advantageous strategy to define and to study population isolates. The isolation of the Alpine populations, together with the extensive data collected so far, make the MICROS study a powerful resource for the study of diseases in many fields of medicine. Recent successes and simulation studies give us confidence that our pedigrees can be valuable both in finding new candidates loci and to confirm existing candidate genes.</p

Linkage and genome-wide association analysis of obesity-related phenotypes: Association of weight with the MGAT1 gene

As major risk-factors for diabetes and cardiovascular diseases, the genetic contribution to obesity-related traits has been of interest for decades. Recently, a limited number of common genetic variants, which have replicated in different populations, have been identified. One approach to increase the statistical power in genetic mapping studies is to focus on populations with increased levels of linkage disequilibrium (LD) and reduced genetic diversity. We have performed joint linkage and genome-wide association analyses for weight and BMI in 3,448 (linkage) and 3,925 (association) partly overlapping healthy individuals from five European populations. A total of four chromosomal regions (two for weight and two for BMI) showed suggestive linkage (lod >2.69) either in one of the populations or in the joint data. At the genome-wide level (nominal P <1.6 × 10 7, Bonferroni-adjusted P 0.05) one single-nucleotide polymorphism (SNP) (rs12517906) (nominal P = 7.3 × 10-8) was associated with weight, whereas none with BMI. The SNP associated with weight is located close to MGAT1. The monoacylglycerol acyltransferase (MGAT) enzyme family is known to be involved in dietary fat absorption. There was no overlap between the linkage regions and the associated SNPs. Our results show that genetic effects influencing weight and BMI are shared across diverse European populations, even though some of these populations have experienced recent population bottlenecks and/or been affected by genetic drift. The analysis enabled us to identify a new candidate gene, MGAT1, associated with weight in women

Common variants in the JAZF1 gene associated with height identified by linkage and genome-wide association analysis

Genes for height have gained interest for decades, but only recently have candidate genes started to be identified. We have performed linkage analysis and genome-wide association for height in approximately 4000 individuals from five European populations. A total of five chromosomal regions showed suggestive linkage and in one of these regions, two SNPs (rs849140 and rs1635852) were associated with height (nominal P = 7.0 × 10−8 and P = 9.6 × 10−7, respectively). In total, five SNPs across the genome showed an association with height that reached the threshold of genome-wide significance (nominal P < 1.6 × 10−7). The association with height was replicated for two SNPs (rs1635852 and rs849140) using three independent studies (n = 31 077, n=1268 and n = 5746) with overall meta P-values of 9.4 × 10−10 and 5.3 × 10−8. These SNPs are located in the JAZF1 gene, which has recently been associated with type II diabetes, prostate and endometrial cancer. JAZF1 is a transcriptional repressor of NR2C2, which results in low IGF1 serum concentrations, perinatal and early postnatal hypoglycemia and growth retardation when knocked out in mice. Both the linkage and association analyses independently identified the JAZF1 region affecting human height. We have demonstrated, through replication in additional independent populations, the consistency of the effect of the JAZF1 SNPs on height. Since this gene also has a key function in the metabolism of growth, JAZF1 represents one of the strongest candidates influencing human height identified so far

Penetrances of breast and ovarian cancer in a large series of families tested for BRCA1/2 mutations.

Accurate estimates of breast and ovarian cancer penetrance in BRCA1/2 mutation carriers are crucial in genetic counseling. Estimation is difficult because of the low frequency of mutated alleles and the often-uncertain mechanisms of family ascertainment. We estimated the penetrances of breast and ovarian cancers in carriers of BRCA1/2 mutations by maximizing the retrospective likelihood of the genetic model, given the observed test results, in 568 Italian families screened for germline mutations. The software BRCAPRO was used as a probability calculation tool in a Markov Chain Monte Carlo approach. Breast cancer penetrances were 27\% (95\% CI 20-34\%) at age 50 years and 39\% (27-52\%) at age 70 in BRCA1 carriers, and 26\% (0.18-0.34\%) at age 50 and 44\% (29-58\%) at age 70 in BRCA2 carriers, and ovarian cancer penetrances were 14\% (7-22\%) at age 50 and 43\% (21-66\%) at age 70 in BRCA1 carriers and 3\% (0-7\%) at age 50 and 15\% (4-26\%) at age 70 in BRCA2 carriers. The new model gave a better fit than the current default in BRCAPRO, the likelihood being 70 log units greater; in addition, the observed numbers of mutations in families stratified by gene and by cancer profile were not significantly different from those expected. Our new penetrance functions are appropriate for predicting breast cancer risk, and for determining the probability of carrying BRCA1/2 mutations, in people who are presently referred to genetic counseling in Italy. Our approach could lead to country-customized versions of the BRCAPRO software by providing appropriate population-specific estimates

Drawing the history of the Hutterite population on a genetic landscape: inference from Y-chromosome and mtDNA genotypes

Although the North American Hutterites trace their origins to South Tyrol, no attempts have been made to examine the genetic migration history of the Hutterites before emigrating to the United States in the 1870s. To investigate this, we studied 9 microsatellite loci and 11 unique event polymorphism (UEP) markers on the Y-chromosome, the hypervariable region I (HVRI) of the mitochondrial DNA (mtDNA), as well as the complete mtDNA genome of Hutterite and South Tyrolean samples. Only 6 out of 14 Y-chromosome UEP+microsatellite haplotypes and 3 out of 11 mitochondrial haplotypes that were present in the Hutterites were also present in the South Tyrolean population. The phylogenetic relationships inferred from Y-chromosome and mtDNA databases show that the Hutterites have a unique genetic background related to a similar extent to central and eastern European populations. An admixture analysis indicates, however, a relatively high genetic contribution of central European populations to the Hutterite gene pool. These results are consistent with historical records on Hutterite migrations and demographic history. In addition, our data reveal similar numbers of Y and mitochondrial haplotypes in Hutterite male and female founders, respectively. The Hutterite male and female gene pools are similar with respect to genetic diversity and genetic distance measures and comparable with respect to their origins, suggesting a similar evolutionary history