Major histocompatibility complex class I chain-related gene A polymorphisms and extended haplotypes are associated with familial alopecia areata.

Alopecia areata (AA) is characterized by hair loss in patches and may progress to total loss of scalp hair, or total loss of scalp and body hair. The major histocompatibility complex (HLA) is associated with susceptibility to AA, as well as other autoimmune diseases. In addition to HLA molecules, non-HLA molecules including the major histocompatibility complex class I chain-related gene A (MICA), a stress-inducible antigen, are also associated with several autoimmune diseases.

Summary of contributions to GAW Group 12: multivariate methods.

Here we summarize the contributions to Group 12 of Genetic Analysis Workshop (GAW) 14, held in Noordwijkerhout, The Netherlands. The theme of this group, multivariate methods, covered a broad range of statistical applications. Most of the contributors considered Problem 1 of the GAW.

A genome-wide linkage scan for ankle-brachial index in African American and non-Hispanic white subjects participating in the GENOA study.

Little is known about the genetics of peripheral arterial disease (PAD). We performed linkage analyses to identify genomic regions that influence ankle-brachial index (ABI), a measure of PAD, in 1310 African Americans (AA) (mean age 62+/-9 years) and 796 non-Hispanic whites (NHW) (mean age 58+/-9 years) belonging to hypertensive sibships. ABI was determined at two sites in each lower extremity and the lower of the two average ABIs was used in the analyses after adjustment for age, age(2), sex, weight, total cholesterol, HDL cholesterol, and ever-smoking.

High-resolution whole-genome association study of Parkinson disease.

We performed a two-tiered, whole-genome association study of Parkinson disease (PD). For tier 1, we individually genotyped 198,345 uniformly spaced and informative single-nucleotide polymorphisms (SNPs) in 443 sibling pairs discordant for PD. For tier 2a, we individually genotyped 1,793 PD-associated SNPs (P<.

CCR5Delta32 polymorphism effects on CCR5 expression, patterns of immunopathology and disease course in multiple sclerosis.

Four distinct patterns of tissue injury have been described in multiple sclerosis (MS) lesions. Infiltrating monocytes in lesions of all patterns co-express CCR1 and CCR5. However, in pattern II lesions, the number of CCR1 cells is decreased, while the number of CCR5 expressing cells is increased in late active versus early active regions.

Two major QTLs and several others relate to factors of metabolic syndrome in the family blood pressure program.

Genome-wide variance components linkage analysis was performed on 4 latent factors underlying metabolic syndrome derived from 10 risk factors. The latent factors represent obesity and insulin, blood pressure, lipids and insulin, and central obesity. The metabolic syndrome factor scores were derived in 4 ethnic groups recruited in 3 Networks of the Family Blood Pressure Program: GENOA (blacks, Hispanics, and whites), HyperGEN (blacks and whites), SAPPHIRe (Asians).

A novel quantitative trait locus on chromosome 1 with pleiotropic effects on HDL-cholesterol and LDL particle size in hypertensive sibships.

Background: High-density lipoprotein (HDL)-cholesterol, triglycerides, and LDL particle size are correlated lipid traits. Abnormal levels of these traits are frequent in hypertensive individuals and contribute to increased risk of coronary heart disease (CHD). We performed univariate and bivariate linkage analyses to identify genomic regions that influence levels of these traits and exert pleiotropic effects on the traits in hypertensive sibships.

Probability of pancreatic cancer following diabetes: a population-based study.

Background & Aims: Although diabetes occurs frequently in pancreatic cancer, the value of new-onset diabetes as a marker of underlying pancreatic cancer is unknown.

Methods: We assembled a population-based cohort of 2122 Rochester, Minnesota, residents age > or =50 years who first met standardized criteria for diabetes between January 1, 1950, and December 31, 1994, and identified those who developed pancreatic cancer within 3 years of meeting criteria for diabetes. We compared observed rates of pancreatic cancer with expected rates based on the Iowa Surveillance Epidemiology and End Results registry.

Genomic loci with pleiotropic effects on coronary artery calcification.

We measured 381 genomewide markers and performed genetic linkage analyses in search of loci influencing coronary artery calcification (CAC), a measure of atherosclerosis determined by electron beam computed tomography, in 948 non-Hispanic white siblings (mean age [+/-standard deviation] = 59.6 +/- 9.9 years; 73.

Alpha1-antitrypsin and neutrophil elastase imbalance and lung cancer risk.

Objective: Imbalance between alpha(1)-antitrypsin and neutrophil elastase is an underlying cause of lung tissue damage that may create a favorable host environment for carcinogenesis. We conducted a case-control study to investigate whether genetic variations indicative of alpha(1)-antitrypsin deficiency (A1ATD) or an excess of neutrophil elastase modify lung cancer risk

Design: The case patients were 305 consecutively identified primary lung cancer patients, and the control subjects were 338 community residents. Protease inhibitor-1 (PI1), encoding alpha(1)-antitrypsin, was typed by an isoelectric focusing assay.

Risk of malignancy in first-degree relatives of patients with pancreatic carcinoma.

Background: Approximately 5-10% of pancreatic carcinoma (PC) patients report a family history of the disease. In some families, mutations of tumor suppressor genes have been elucidated, but for most the causative gene remains unidentified. Counseling the families of PC patients regarding their risk of cancer remains problematic because little information is available.

UCHL1 is associated with Parkinson's disease: a case-unaffected sibling and case-unrelated control study.

To avoid the possible confounding effect of population stratification, we employed a discordant sibling study design and a liberalization of the sibling transmission disequilibrium test to confirm the association of the S18Y variant of the ubiquitin carboxi-terminal hydrolase L1 (UCHL1) gene with Parkinson's disease (PD). The study included 497 case-control pairs (427 case-unaffected sibling pairs and 70 case-unrelated control pairs). Analyses confirmed a significant inverse association of the UCHL1 S18Y polymorphism with PD overall (OR=0.

Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X.

Context: Approximately 60% of families that meet the Amsterdam-I criteria (AC-I) for hereditary nonpolyposis colorectal cancer (HNPCC) have a hereditary abnormality in a DNA mismatch repair (MMR) gene. Cancer incidence in AC-I families with MMR gene mutations is reported to be very high, but cancer incidence for individuals in AC-I families with no evidence of an MMR defect is unknown.

Objective: To determine if cancer risks in AC-I families with no apparent deficiency in DNA MMR are different from cancer risks in AC-I families with DNA MMR abnormalities.

Thrombomodulin gene polymorphisms or haplotypes as potential risk factors for venous thromboembolism: a population-based case-control study.

Dysfunction of the protein C anticoagulant system is associated with venous thromboembolism (VTE) and thrombomodulin (TM) is a critical cofactor within the protein C system. The aim of this study was to test the hypotheses that polymorphisms or haplotypes within the TM gene are common risk factors for VTE. We screened the TM putative promoter, exon and 3'-untranslated region for sequence variations in a random sample (n = 266) of consecutive idiopathic, objectively confirmed non-Olmsted County VTE patients referred to the Mayo Clinic.

Interaction of alpha-synuclein and tau genotypes in Parkinson's disease.

To determine whether the microtubule-associated protein tau (MAPT) and alpha-synuclein (SNCA) genes interact to confer Parkinson's disease (PD) susceptibility, we conducted a study of 557 case-control pairs. There was an increased risk of PD for persons with either SNCA 261/261 or MAPT H1/H1 genotypes as compared with persons with neither (odds ratio, 1.96; 95% confidence interval, 1.

Genomic susceptibility loci for brain atrophy in hypertensive sibships from the GENOA study.

We measured 366 microsatellite markers genome-wide to search for loci contributing to subcortical white matter ischemic damage (leukoariosis) and brain atrophy in 488 non-Hispanic white subjects (193 men, 295 women; mean age+/-SD=64.1+/-7.7 years; 79% hypertensive) from 223 sibships recruited through > or =2 members with essential hypertension diagnosed before age 60.

Germ line Fanconi anemia complementation group C mutations and pancreatic cancer.

Biallelic mutations in Fanconi anemia complementation group genes disrupt DNA repair and result in the complex Fanconi anemia phenotype. In addition, germ line mutations in the BRCA2/FANCD1 Fanconi anemia complementation group gene have also been implicated in predisposition to a number of cancers including pancreatic cancer. The recent identification of FANCC and FANCG mutations in resected pancreatic tumors selected for loss of heterozygosity on chromosome 9, some of which were present in the germ line DNA, suggests that inactivation of these and other Fanconi complementation group genes may contribute to pancreatic cancer.

Pleiotropic genetic effects contribute to the correlation between HDL cholesterol, triglycerides, and LDL particle size in hypertensive sibships.

Objective: Abnormalities of HDL cholesterol (HDL-C), triglycerides, and LDL particle size are present in familial dyslipidemic hypertension. We investigated heritability of these three lipid traits and the extent to which shared effects of genes (pleiotropy) contribute to the additive genetic variation in each trait in hypertensive sibships.

Methods: Subjects included 788 individuals (60% women) ascertained through sibships with >/=2 members diagnosed with hypertension before age 60 years.

Human brain derived neurotrophic factor (BDNF) genes, splicing patterns, and assessments of associations with substance abuse and Parkinson's Disease.

Potential roles for variants in the human BDNF gene in human brain disorders are supported by findings that include: (a) influences that this trophic factor can exert on important neurons, brain regions, and neurotransmitter systems, (b) changes in BDNF expression that follow altered neuronal activity and drug treatments, and (c) linkages or associations between genetic markers in or near BDNF and human traits and disorders that include depression, schizophrenia, addictions, and Parkinson's disease. We now report assembly of more than 70 kb of BDNF genomic sequence, delineation of 7 noncoding and 1 coding human BDNF exons, elucidation of BDNF transcripts that are initiated at several alternative promoters, identification of BDNF mRNA splicing patterns, elucidation of novel sequences that could contribute to activity-dependent BDNF mRNA transcription, targeting and/or translation, elucidation of tissue-specific and brain-region-specific use of the alternative human BDNF promoters and splicing patterns, identification of single nucleotide polymorphism (SNP), and simple sequence length polymorphism (SSLP) BDNF genomic variants and identification of patterns of restricted haplotype diversity at the BDNF locus. We also identified type 2 BDNF-locus transcripts that are coded by a novel gene that is overlapped with type 1 BDNF gene and transcribed in reverse orientation with several alternative splicing isoforms.

Elevated amyloid beta protein (Abeta42) and late onset Alzheimer's disease are associated with single nucleotide polymorphisms in the urokinase-type plasminogen activator gene.

Plasma amyloid beta protein (Abeta42) levels and late onset Alzheimer's disease (LOAD) have been linked to the same region on chromosome 10q. The PLAU gene within this region encodes urokinase-type plasminogen activator, which converts plasminogen to plasmin. Abeta aggregates induce PLAU expression thereby increasing plasmin, which degrades both aggregated and non-aggregated forms of Abeta.

Random-effects Cox proportional hazards model: general variance components methods for time-to-event data.

Proportional hazards regression models are commonly used to study factors associated with time-to-event data. Because many complex genetic diseases exhibit variation in age at onset, it is important to have the capability to perform survival analyses on data collected from individuals whose observations are correlated due to shared genes or environment. While there are widely accepted methods for variance components analysis for simple quantitative traits, a parallel methodology for survival data has not been available.

Multivariate linkage analysis of blood pressure and body mass index.

Multivariate linkage analyses of correlated traits provide greater statistical power to identify genetic loci with effects too small to be detected in single trait analyses. We conducted genomewide multivariate analyses of systolic BP, diastolic BP, and body mass index (BMI) in 1,848 non-Hispanic white subjects (968 females, 880 males) from 279 multigenerational pedigrees from Rochester, Minnesota. Blood pressure was measured by random zero sphygmomanometer; body mass index was calculated from measurements of height and weight; and genotypes were measured at 520 microsatellite marker loci distributed across the 22 autosomes.

UCHL1 is a Parkinson's disease susceptibility gene.

The reported inverse association between the S18Y variant of the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene and Parkinson's disease (PD) has strong biological plausibility. If confirmed, genetic association of this variant with PD may support molecular targeting of the UCHL1 gene and its product as a therapeutic strategy for PD. In this light, we performed a collaborative pooled analysis of individual-level data from all 11 published studies of the UCHL1 S18Y gene variant and PD.

Screening the genome to detect an association with hypertension.

We report tree-based association analysis as applied to the two Framingham cohorts and to the first replication of the simulated data obtained from the Genetic Analysis Workshop 13. For this analysis, familial association is ignored. The two endpoints examined are hypertension status at initial visit and time-to-hypertension, using a censored data approach.

Localization of genes involved in the metabolic syndrome using multivariate linkage analysis.

There are no well accepted criteria for the diagnosis of the metabolic syndrome. However, the metabolic syndrome is identified clinically by the presence of three or more of these five variables: larger waist circumference, higher triglyceride levels, lower HDL-cholesterol concentrations, hypertension, and impaired fasting glucose. We use sets of two or three variables, which are available in the Framingham Heart Study data set, to localize genes responsible for this syndrome using multivariate quantitative linkage analysis.