Genetic influences on serum bilirubin in American Indians: The Strong Heart Family Study

Abstract

Objective: To identify genetic variation influencing serum bilirubin levels in American Indians, we performed genome-wide screening and association analyses in the Strong Heart Family Study. Bilirubin is an endogenous antioxidant that has demonstrated an inverse relationship with cardiovascular disease. Genetic variation within the promoter region of uridine diphosphate glucuronosyltransferase (UGT1A1) on chromosome 2q has been associated with elevated serum bilirubin levels in European populations. However, no study has investigated the UGT1A1 promoter in American Indians.

Methods: Statistical analyses were carried out with 3,484 participants aged 14 to 93 years recruited from three geographic areas in the United States; Arizona, Oklahoma, and North and South Dakota.

Results:Variance components linkage analysis detected a quantitative trait locus (QTL) for bilirubin on chromosome 2q in the combined centers (LOD = 6.61, P = 4.24 × 10⁻⁶) and in Oklahoma (LOD = 5.65, P = 4.57 24 × 10⁻⁵). Genetic association of the UGT1A1 promoter polymorphism was significant for all geographic locations. After adjustment using conditional linkage for UGT1A1 promoter variance, the linkage signal dropped to 1.10 in the combined sample and to 3.32 (P = 0.02) in Oklahoma, indicating this polymorphism is not completely responsible for the linkage signal in American Indians. We also detected suggestive linkage signals in the Dakotas on chromosome 10p12 (LOD = 2.18) and in the combined centers (LOD = 2.24) on chromosome 10q21.

Conclusions: Replication of a serum bilirubin QTL on chromosome 2q in American Indians implicates UGT1A1 but further genotyping is warranted to identify additional causative polymorphisms. Evidence also supports a potential novel locus for bilirubin on chromosome 10.

Bivariate genetic association of KIAA1797 with heart rate in American Indians: The Strong Heart Family Study

Abstract

Heart rate (HR) has been identified as a risk factor for cardiovascular disease (CVD), yet little is known regarding genetic factors influencing this phenotype. Previous research in American Indians from the Strong Heart Family Study (SHFS) identified a significant quantitative trait locus (QTL) for HR on chromosome 9p21. Genetic association on HR was conducted in the SHFS. HR was measured from electrocardiogram (ECG) and echocardiograph (Echo) Doppler recordings. We examined 2,248 single nucleotide polymorphisms (SNPs) on chromosome 9p21 for association using a gene-centric statistical test. We replicated the aforementioned QTL (LOD=4.83; genome-wide p= 0.0003) on chromosome 9p21 in one SHFS population using joint linkage of ECG and Echo HR. After correcting for effective number of SNPs using a gene-centric test, six SNPs (rs7875153, rs7848524, rs4446809, rs10964759, rs1125488, and rs7853123) remained significant. We applied a novel bivariate association method, which was a joint test of association of a single locus to two traits using a standard additive genetic model. The SNP, rs7875153, provided the strongest evidence for association (p=7.14x10^-6). This SNP (rs7875153), is rare (minor allele frequency = 0.02) in American Indians and is located within intron 9 of the gene KIAA1797. To support this association we applied lymphocyte RNA expression data from the San Antonio Family Heart Study, a longitudinal study of CVD in Mexican Americans. Expression levels of KIAA1797 were significantly associated (p=0.012) with HR. These findings in independent populations support that KIAA1797 genetic variation may be associated with HR but elucidation of a functional relationship requires additional study.

P365R D20: The Poster (4/9/2008)

Today, I presented my poster at the Human Biology meetings. You can check out a copy of the poster here.

mood disorders and schizophrenia in genetically isolated populations

Chasing genes for mood disorders and schizophrenia in genetically isolated populations

Tine Venken 1 2, Jurgen Del-Favero 1 2 Abstract

Major affective disorders and schizophrenia are among the most common brain diseases worldwide and their predisposition is influenced by a complex interaction of genetic and environmental factors. So far, traditional linkage mapping studies for these complex disorders have not achieved the same success as the positional cloning of genes for Mendelian diseases. The struggle to identify susceptibility genes for complex disorders has stimulated the development of alternative approaches, including studies in genetically isolated populations. Since isolated populations are likely to have both a reduced number of genetic vulnerability factors and environmental background and are therefore considered to be more homogeneous compared to outbred populations, the use of isolated populations in genetic studies is expected to improve the chance of finding susceptibility loci and genes. Here we review the role of isolated populations, based on linkage and association studies, in the identification of susceptibility genes for bipolar disorder and schizophrenia.

Hum Mutat 0, 1-15, 2007. © 2007 Wiley-Liss, Inc.>

Cardiovascular Disease, Framingham and Genetics

The current article of BMC Medical Genetics has a special issue that investigates the genetic associationof 100K SNPs in two generations involved in the Framingham Heart Study. One of the more interesting articles is an association study of cardiovascular disease and these SNPs by Larson et al. (freely available here and abstract below). The amount of information produced by these large gene database studies are pretty impressive due to the amount of information produced. I suppose the only drawback is that the statistical techniques for analyzing them may be a couple of years behind but will catch up soon enough. BTW Henry Greeley has an interesting looking article in the most recent Annual Review of Human Genetics and Genomics regarding the ethical conundrum these large scale gene databases may create or are creating.

Framingham Heart Study 100K project: genome-wide associations
for cardiovascular disease outcomes

Background: Cardiovascular disease (CVD) and its most common manifestations – including coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) – are major causes of morbidity and mortality. In many industrialized countries, cardiovascular disease (CVD) claims more lives each year than any other disease. Heart disease and stroke are the first and third leading causes of death in the United States. Prior investigations have reported several single gene variants associated with CHD, stroke, HF, and AF. We report a community-based genome-wide association study of major CVD outcomes.

Methods: In 1345 Framingham Heart Study participants from the largest 310 pedigrees (54% women, mean age 33 years at entry), we analyzed associations of 70,987 qualifying SNPs (Affymetrix 100K GeneChip) to four major CVD outcomes: major atherosclerotic CVD (n = 142; myocardial infarction, stroke, CHD death), major CHD (n = 118; myocardial infarction, CHD death), AF (n = 151), and HF (n = 73). Participants free of the condition at entry were included in proportional hazards models. We analyzed model-based deviance residuals using generalized estimating equations to test associations between SNP genotypes and traits in additive genetic models restricted to autosomal SNPs with minor allele frequency ≥0.10, genotype call rate ≥0.80, and Hardy-Weinberg equilibrium p-value ≥ 0.001.

Results: Six associations yielded p is less than 10-5. The lowest p-values for each CVD trait were as follows: major CVD, rs499818, p = 6.6 × 10-6; major CHD, rs2549513, p = 9.7 × 10-6; AF, rs958546, p = 4.8 × 10-6; HF: rs740363, p = 8.8 × 10-6. Of note, we found associations of a 13 Kb region on chromosome 9p21 with major CVD (p 1.7 – 1.9 × 10-5) and major CHD (p 2.5 – 3.5 × 10-4) that confirm associations with CHD in two recently reported genome-wide association studies. Also, rs10501920 in CNTN5 was associated with AF (p = 9.4 × 10-6) and HF (p = 1.2 × 10-4). Complete results for these phenotypes can be found at the dbgap website.

Conclusion: No association attained genome-wide significance, but several intriguing findings emerged. Notably, we replicated associations of chromosome 9p21 with major CVD. Additional studies are needed to validate these results. Finding genetic variants associated with CVD may point to novel disease pathways and identify potential targeted preventive therapies