Type 2 diabetes susceptibility single-nucleotide polymorphisms are not associated with polycystic ovary syndrome.

Two cohorts of women with polycystic ovary syndrome (PCOS), comprising 400 probands and affected sisters in 365 families and a case-control group including 395 women with PCOS and 171 healthy women with regular menstrual cycles, were studied to determine whether single-nucleotide polymorphisms (SNPs) identified as susceptibility loci in genomewide association studies of type 2 diabetes are also associated with PCOS. None of the 18 allelic variants in 10 genes previously shown to be associated with type 2 diabetes were found to be associated with PCOS, but some were associated with indices of beta cell function.

FTO and MC4R gene variants are associated with obesity in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women. It is also associated with metabolic disturbances that place women at increased risk for obesity and type 2 diabetes. There is strong evidence for familial clustering of PCOS and a genetic predisposition.

Polymorphic cis- and trans-regulation of human gene expression.

Expression levels of human genes vary extensively among individuals. This variation facilitates analyses of expression levels as quantitative phenotypes in genetic studies where the entire genome can be scanned for regulators without prior knowledge of the regulatory mechanisms, thus enabling the identification of unknown regulatory relationships. Here, we carried out such genetic analyses with a large sample size and identified cis- and trans-acting polymorphic regulators for about 1,000 human genes.

A variant in the fibrillin-3 gene is associated with TGF-β and inhibin B levels in women with polycystic ovary syndrome.

In an attempt to evaluate the association between allele 8 (A8) of D19S884 in the fibrillin-3 gene and circulating transforming growth factor (TGF) β and inhibin levels in women with polycystic ovary syndrome (PCOS), we studied 120 similarly aged women from families with PCOS and compared 40 women with PCOS who did not have A8 (A8- PCOS) with 40 women with PCOS who had A8 (A8+ PCOS) and 40 normally menstruating women who did not have either PCOS or A8 (A8- Non-PCOS). A8- PCOS is associated with higher levels of TGF-β1 compared with A8+ PCOS or A8- Non-PCOS, similar levels of TGF-β2 compared with A8+ PCOS but lower levels of TGF-β2 compared with A8- Non-PCOS, and lower levels of inhibin B and aldosterone compared with A8+ PCOS.

A latent class model for testing for linkage and classifying families when the sample may contain segregating and non-segregating families.

In a quantitative trait locus (QTL) study, it is usually not feasible to select families with offspring that simultaneously display variability in more than one phenotype. When multiple phenotypes are of interest, the sample will, with high probability, contain 'non-segregating' families, i.e.

Gene expression and genetic variation in response to endoplasmic reticulum stress in human cells.

The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) results in the condition called "ER stress," which induces the unfolded protein response (UPR), a complex cellular process that includes changes in expression of many genes. Failure to restore homeostasis in the ER is associated with human diseases. To identify the underlying changes in gene expression in response to ER stress, we induced ER stress in human B cells and then measured gene expression at ten time points.

Family-based analysis of candidate genes for polycystic ovary syndrome.

Context: Polycystic ovary syndrome (PCOS) is a complex disorder having both genetic and environmental components. A number of association studies based on candidate genes have reported significant association, but few have been replicated. D19S884, a polymorphic marker in fibrillin 3 (FBN3), is one of the few association findings that has been replicated in independent sets of families.

Coexpression network based on natural variation in human gene expression reveals gene interactions and functions.

Genes interact in networks to orchestrate cellular processes. Analysis of these networks provides insights into gene interactions and functions. Here, we took advantage of normal variation in human gene expression to infer gene networks, which we constructed using correlations in expression levels of more than 8.

Genetics of human gene expression: mapping DNA variants that influence gene expression.

There is extensive natural variation in human gene expression. As quantitative phenotypes, expression levels of genes are heritable. Genetic linkage and association mapping have identified cis- and trans-acting DNA variants that influence expression levels of human genes.

PDE8A genetic variation, polycystic ovary syndrome and androgen levels in women.

Polycystic ovary syndrome (PCOS) is characterized by excessive theca cell androgen secretion, dependent upon LH, which acts through the intermediacy of 3',5'-cyclic adenosine monophosphate (cAMP). cAMP signaling pathways are controlled through regulation of its synthesis by adenylyl cyclases, and cAMP degradation by phosphodiesterases (PDEs). PDE8A, a high-affinity cAMP-specific PDE is expressed in the ovary and testis.

Effects of cis and trans genetic ancestry on gene expression in African Americans.

Variation in gene expression is a fundamental aspect of human phenotypic variation. Several recent studies have analyzed gene expression levels in populations of different continental ancestry and reported population differences at a large number of genes. However, these differences could largely be due to non-genetic (e.

A review of family-based tests for linkage disequilibrium between a quantitative trait and a genetic marker.

Quantitative trait transmission/disequilibrium tests (quantitative TDTs) are commonly used in family-based genetic association studies of quantitative traits. Despite the availability of various quantitative TDTs, some users are not aware of the properties of these tests and the relationships between them. This review aims at outlining the broad features of the various quantitative TDT procedures carried out in the frequently used QTDT and FBAT packages.

Disease associations and family-based tests.

This unit describes the statistical techniques necessary for performing family-based association studies (such as the TDT) for genetic polymorphisms. Such studies have become increasingly important in the identification of genes that confer an increased risk to disease, particularly for common diseases with a complex etiology. The family-based approach avoids some of the problems often encountered when applying the traditional case-control design to genetic studies.

Monozygotic twins reveal germline contribution to allelic expression differences.

Variation in the level of gene expression is a major determinant of a cell's function and characteristics. Common allelic variants of genes can be expressed at different levels and thus contribute to phenotypic diversity. We have measured allelic expression differences at heterozygous loci in monozygotic twins and in unrelated individuals.

Genetic heterogeneity and trans regulators of gene expression.

Heterogeneity poses a challenge to linkage mapping. Here, we apply a latent class extension of Haseman-Elston regression to expression phenotypes with significant evidence of linkage to trans regulators in 14 large pedigrees. We test for linkage, accounting for heterogeneity, and classify individual families as "linked" and "unlinked" on the basis of their contribution to the overall evidence of linkage.

Data for Genetic Analysis Workshop (GAW) 15, Problem 1: genetics of gene expression variation in humans.

Here we describe the data provided for Problem 1 of Genetic Analysis Workshop 15. The data provided for Problem 1 were unusual in two ways. First, the phenotype was the level of gene expression for each gene, not a conventional phenotype like height or disease, and second, there were more than 3500 such phenotypes.

Disease associations and family-based tests.

This unit describes the statistical techniques necessary for performing family-based association studies (e.g., the TDT) for genetic polymorphisms.

Introduction to Genetic Analysis Workshop 15 summaries.

The 15th biennial Genetic Analysis Workshop (GAW15) took place November 11-15, 2006 in St. Pete Beach, Florida. The workshop's primary focus was on the appropriate linkage, association, and other analyses of the increasingly large datasets generated by genetics research.

Ovulatory response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene.

Context: Clomiphene and insulin sensitizers such as metformin are used to induce ovulation in polycystic ovary syndrome (PCOS), but the ovulatory response is variable, and the causes of this variation are poorly understood.

Objective: Our objective was to identify predictive genetic polymorphisms and other determinants of ovulatory response.

Design: This was a substudy of a multicenter randomized clinical trial.

Common genetic variants account for differences in gene expression among ethnic groups.

Variation in DNA sequence contributes to individual differences in quantitative traits, but in humans the specific sequence variants are known for very few traits. We characterized variation in gene expression in cells from individuals belonging to three major population groups. This quantitative phenotype differs significantly between European-derived and Asian-derived populations for 1,097 of 4,197 genes tested.

What is the significance of a significant TDT?

This note summarizes the development of the transmission/disequilibrium test (TDT). The initial purpose of the TDT procedure was to test for linkage between a genetic marker and a disease susceptibility locus when an association had been found between the two. An association between disease and marker had sometimes been taken to imply linkage.

Mapping determinants of human gene expression by regional and genome-wide association.

To study the genetic basis of natural variation in gene expression, we previously carried out genome-wide linkage analysis and mapped the determinants of approximately 1,000 expression phenotypes. In the present study, we carried out association analysis with dense sets of single-nucleotide polymorphism (SNP) markers from the International HapMap Project. For 374 phenotypes, the association study was performed with markers only from regions with strong linkage evidence; these regions all mapped close to the expressed gene.

Assessment of 115 candidate genes for diabetic nephropathy by transmission/disequilibrium test.

Several lines of evidence, including familial aggregation, suggest that allelic variation contributes to risk of diabetic nephropathy. To assess the evidence for specific susceptibility genes, we used the transmission/disequilibrium test (TDT) to analyze 115 candidate genes for linkage and association with diabetic nephropathy. A comprehensive survey of this sort has not been undertaken before.

The keeshond defect in cardiac conotruncal development is oligogenic.

Earlier studies in the keeshond breed of dogs established that isolated conotruncal defects (CTDs) are a group of genetically and embryologically related cardiac malformations, including sub-clinical defects of the conal septum, conal ventricular septal defects, tetralogy of Fallot, and persistent truncus arteriosus. The same spectrum occurs in some human families. In both species, inheritance of non-syndromic CTDs is usually complex and multifactorial inheritance has been assumed.