The fibromyalgia family study: a genome-wide linkage scan study.

Objective: Familial aggregation of fibromyalgia has been increasingly recognized. The goal of this study was to conduct a genome-wide linkage scan to identify susceptibility loci for fibromyalgia.

Methods: We genotyped members of 116 families from the Fibromyalgia Family Study and performed a model-free genome-wide linkage analysis of fibromyalgia with 341 microsatellite markers, using the Haseman-Elston regression approach.

Candidate-gene association study of mothers with pre-eclampsia, and their infants, analyzing 775 SNPs in 190 genes.

Pre-eclampsia (PE) affects 5-7% of pregnancies in the US, and is a leading cause of maternal death and perinatal morbidity and mortality worldwide. To identify genes with a role in PE, we conducted a large-scale association study evaluating 775 SNPs in 190 candidate genes selected for a potential role in obstetrical complications. SNP discovery was performed by DNA sequencing, and genotyping was carried out in a high-throughput facility using the MassARRAY(TM) System.

Prediction of empirical p values from asymptotic p values for conditional logistic affected relative pair linkage analysis.

Objective: p Values are inaccurate for model-free linkage analysis using the conditional logistic model if we assume that the LOD score is asymptotically distributed as a simple mixture of chi-square distributions. When analyzing affected relative pairs alone, permuting the allele sharing of relative pairs does not lead to a useful permutation distribution. As an alternative, we have developed regression prediction models that provide more accurate p values.

Genetic linkage of systemic lupus erythematosus to 13q32 in African American families with affected male members.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder involving genetic and environmental factors. Previously, our group showed that SLE females with affected male relatives have higher prevalence of renal disease than SLE females with no affected male relatives in a sample of 372 individuals from 159 families. By adding 392 individuals from 181 new families, we replicated this finding in the largest collection of families with affected males, confirming our hypothesis that multiplex SLE families with at least one affected male member ("male families") comprise a distinct subpopulation of SLE multiplex families.

Tapasin gene polymorphism in systemic onset juvenile rheumatoid arthritis: a family-based case-control study.

Juvenile rheumatoid arthritis (JRA) comprises a group of chronic systemic inflammatory disorders that primarily affect joints and can cause long-term disability. JRA is likely to be a complex genetic trait, or a series of such traits, with both genetic and environmental factors contributing to the risk for developing the disease and to its progression. The HLA region on the short arm of chromosome 6 has been intensively evaluated for genetic contributors to JRA, and multiple associations, and more recently linkage, has been detected.

The Family Investigation of Nephropathy and Diabetes (FIND): design and methods.

Background: The Family Investigation of Nephropathy and Diabetes (FIND) is a multicenter study designed to identify genetic determinants of diabetic nephropathy. It is conducted in eight U.S.

Using overall allele-sharing to detect the presence of large-scale data errors and parameter misspecification in sib-pair linkage studies.

Data errors and marker allele frequency misspecification can lead to incorrect inference in linkage analysis. Here we demonstrate the effect of each on an allele-sharing statistic in a sample of sib pairs. In the context of relationship testing, we propose a new test that compares the sample genome-wide sib-pair allele sharing to its expectation and show that this test can detect the presence of large-scale data and model errors.

Dense genome-wide linkage analysis of rheumatoid arthritis, including covariates.

Objective: Rheumatoid arthritis (RA) is a heterogeneous disease that exhibits a complex genetic component. Previous RA genome scans confirmed the involvement of the HLA region and generated data on suggestive signals at non-HLA regions, albeit with few overlaps in findings between studies. The present study was undertaken to detect potential RA gene regions and to estimate the number of true RA gene regions, taking into account the heterogeneity of RA, through performance of a dense genome scan.

Genome scan for familial abdominal aortic aneurysm using sex and family history as covariates suggests genetic heterogeneity and identifies linkage to chromosome 19q13.

Background: Abdominal aortic aneurysm (AAA) is a relatively common disease, with 1% to 2% of the population harboring aneurysms. Genetic risk factors are likely to contribute to the development of AAAs, although no such risk factors have been identified.

Methods And Results: We performed a whole-genome scan of AAA using affected-relative-pair (ARP) linkage analysis that includes covariates to allow for genetic heterogeneity.

Evidence of linkage and association on chromosome 20 for late-onset Alzheimer disease.

Recently, we reported evidence of linkage on chromosome 20 for Alzheimer disease (AD) using a novel statistical approach to incorporate covariates (e.g., age, ApoE genotype) into the analysis.

Interaction of gender and body mass index (BMI) reveals evidence of linkage for hypertension in the Framingham Heart Study.

Background: Genetic heterogeneity and complex biologic mechanisms of blood pressure regulation pose significant challenges to the identification of susceptibility loci influencing hypertension. Previous linkage studies have reported regions of interest, but lack consistency across studies. Incorporation of covariates, in particular the interaction between two independent risk factors (gender and BMI) greatly improved our ability to detect linkage.

Intracranial aneurysms in Finnish families: confirmation of linkage and refinement of the interval to chromosome 19q13.3.

We recently reported a two-stage genomewide screen of 48 sib pairs affected with intracranial aneurysms (IAs) that revealed suggestive linkage to chromosome 19q13, with a LOD score of 2.58. The region supporting linkage spanned approximately 22 cM.

Effects of covariates: a summary of Group 5 contributions.

This report summarizes the contributions of Genetic Analysis Workshop 13 (GAW13) related to the use of covariates in genetic analysis. Seven papers are summarized, five of which analyzed the Framingham Heart Study Data, and two the simulated data. Five papers examined the role of covariates in linkage analysis, using a variety of statistical approaches including affected sibling pair analysis, conditional logistic regression, and variance components methods.

Regression models for linkage: issues of traits, covariates, heterogeneity, and interaction.

Regression methods offer a common framework to analyze linkage for quantitative trait loci as well as linkage for affection status using affected sib-pairs. Although numerous papers on regression methods for linkage have been published, some common themes and important caveats tend to be scattered across the literature. For example, the typical approach is to regress a function of traits on identical-by-descent (IBD) information, but the reversal (regression of IBD on a function of traits) offers important insights.

Linkage analysis of candidate loci for end-stage renal disease due to diabetic nephropathy.

Diabetic nephropathy (DN), a major cause of ESRD, is undoubtedly multifactorial and is caused by environmental and genetic factors. To identify a genetic basis for DN susceptibility, we are collecting multiplex DN families in the Caucasian (CA) and African-American (AA) populations for whole genome scanning and candidate gene analysis. A candidate gene search of diabetic sibs discordantly affected, concordantly affected and concordantly unaffected for DN was performed with microsatellite markers in genomic regions suspected to harbor nephropathy susceptibility loci.

MMP13 promoter polymorphism is associated with atherosclerosis in the abdominal aorta of young black males.

Previous studies suggested that remodeling of connective tissue is important in progression of atherosclerosis. We investigated the importance of matrix metalloproteinase 13 (MMP13), in the pathogenesis of atherosclerosis using 995 samples from the Pathobiological Determinants of Atherosclerosis in Youth collection in an association study. We identified two new MMP13 promoter polymorphisms.

Search for intracranial aneurysm susceptibility gene(s) using Finnish families.

Background: Cerebrovascular disease is the third leading cause of death in the United States, and about one-fourth of cerebrovascular deaths are attributed to ruptured intracranial aneurysms (IA). Epidemiological evidence suggests that IAs cluster in families, and are therefore probably genetic. Identification of individuals at risk for developing IAs by genetic tests will allow concentration of diagnostic imaging on high-risk individuals.

A second locus for very-late-onset Alzheimer disease: a genome scan reveals linkage to 20p and epistasis between 20p and the amyloid precursor protein region.

We used a covariate-based linkage method to reanalyze genome scan data from affected sibships collected by the Alzheimer Disease (AD) Genetics Initiative of the National Institute of Mental Health. As reported in an earlier article, the amyloid-beta precursor protein (APP) region is strongly linked to affected sib pairs of the oldest current age (i.e.

Segregation at three loci explains familial and population risk in Hirschsprung disease.

Hirschsprung disease (HSCR), the most common hereditary cause of intestinal obstruction, shows considerable variation and complex inheritance. Coding sequence mutations in RET, GDNF, EDNRB, EDN3 and SOX10 lead to long-segment (L-HSCR) and syndromic HSCR but fail to explain the transmission of the much more common short-segment form (S-HSCR). We conducted a genome scan in families with S-HSCR and identified susceptibility loci at 3p21, 10q11 and 19q12 that seem to be necessary and sufficient to explain recurrence risk and population incidence.

The linkage information content value of polymorphism genetic markers in model-free linkage analysis.

Guo and Elston [Hum Hered 1999;49:112-118] developed a linkage information content (LIC) value to measure the informativeness of a marker for identity-by-descent (IBD) sharing status of relative pairs. LIC values were derived for five types of relative pairs: full sib, half sib, grandparent-grandchild, first cousin and avuncular. In this paper, we give corrected LIC values for full sib, grandparent-grandchild, first cousin and avuncular pairs, and indicate the availability of a computer program to calculate them.

Increased prevalence of renal disease in systemic lupus erythematosus families with affected male relatives.

Objective: To distinguish familial differences from sex-related differences in the clinical manifestations of systemic lupus erythematosus (SLE).

Methods: A total of 372 affected individuals from 160 multiplex SLE pedigrees were analyzed. Twenty-five of these pedigrees contained at least 1 affected male relative.