Biomedical subjects

Dennis G Ballinger

Publications and source records attributed to Dennis G Ballinger.

11 recordsLinked to original sources

PubMed2006

Novel genes identified in a high-density genome wide association study for nicotine dependence.

Tobacco use is a leading contributor to disability and death worldwide, and genetic factors contribute in part to the development of nicotine dependence. To identify novel genes for which natural variation contributes to the development of nicotine dependence, we performed a comprehensive genome wide association study using nicotine dependent smokers as cases and non-dependent smokers as controls. To allow the efficient, rapid, and cost effective screen of the genome, the study was carried out using a two-stage design. In the first stage, genotyping of over 2.4 million single nucleotide polymorphisms (SNPs) was completed in case and control pools. In the second stage, we selected SNPs for individual genotyping based on the most significant allele frequency differences between cases and controls from the pooled results. Individual genotyping was performed in 1050 cases and 879 controls using 31 960 selected SNPs. The primary analysis, a logistic regression model with covariates of age, gender, genotype and gender by genotype interaction, identified 35 SNPs with P-values less than 10(-4) (minimum P-value 1.53 x 10(-6)). Although none of the individual findings is statistically significant after correcting for multiple tests, additional statistical analyses support the existence of true findings in this group. Our study nominates several novel genes, such as Neurexin 1 (NRXN1), in the development of nicotine dependence while also identifying a known candidate gene, the beta3 nicotinic cholinergic receptor. This work anticipates the future directions of large-scale genome wide association studies with state-of-the-art methodological approaches and sharing of data with the scientific community.

Case-Control Studies↗

PubMed2006

Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs.

Nicotine dependence is one of the world's leading causes of preventable death. To discover genetic variants that influence risk for nicotine dependence, we targeted over 300 candidate genes and analyzed 3713 single nucleotide polymorphisms (SNPs) in 1050 cases and 879 controls. The Fagerström test for nicotine dependence (FTND) was used to assess dependence, in which cases were required to have an FTND of 4 or more. The control criterion was strict: control subjects must have smoked at least 100 cigarettes in their lifetimes and had an FTND of 0 during the heaviest period of smoking. After correcting for multiple testing by controlling the false discovery rate, several cholinergic nicotinic receptor genes dominated the top signals. The strongest association was from an SNP representing CHRNB3, the beta3 nicotinic receptor subunit gene (P = 9.4 x 10(-5)). Biologically, the most compelling evidence for a risk variant came from a non-synonymous SNP in the alpha5 nicotinic receptor subunit gene CHRNA5 (P = 6.4 x 10(-4)). This SNP exhibited evidence of a recessive mode of inheritance, resulting in individuals having a 2-fold increase in risk of developing nicotine dependence once exposed to cigarette smoking. Other genes among the top signals were KCNJ6 and GABRA4. This study represents one of the most powerful and extensive studies of nicotine dependence to date and has found novel risk loci that require confirmation by replication studies.

Adult↗

PubMed2006

A genomewide single-nucleotide-polymorphism panel with high ancestry information for African American admixture mapping.

Admixture mapping requires a genomewide panel of relatively evenly spaced markers that can distinguish the ancestral origins of chromosomal segments in admixed individuals. Through use of the results of the International HapMap Project and specific selection criteria, the current study has examined the ability of selected single-nucleotide polymorphisms (SNPs) to extract continental ancestry information in African American subjects and to explore parameters for admixture mapping. Genotyping of two linguistically diverse West African populations (Bini and Kanuri Nigerians, who are Niger-Congo [Bantu] and Nilo-Saharan speakers, respectively), European Americans, and African Americans validated a genomewide set of >4,000 SNP ancestry-informative markers with mean and median F(ST) values >0.59 and mean and median Fisher's information content >2.5. This set of SNPs extracted a larger amount of ancestry information in African Americans than previously reported SNP panels and provides nearly uniform coverage of the genome. Moreover, in the current study, simulations show that this more informative panel improves power for admixture mapping in African Americans when ethnicity risk ratios are modest. This is particularly important in the application of admixture mapping in complex genetic diseases for which only modest ethnicity risk ratios of relevant susceptibility genes are expected.

Black or African American↗

PubMed2006

Analysis of allelic differential expression in human white blood cells.

Allelic variation of gene expression is common in humans, and is of interest because of its potential contribution to variation in heritable traits. To identify human genes with allelic expression differences, we genotype DNA and examine mRNA isolated from the white blood cells of 12 unrelated individuals using oligonucleotide arrays containing 8406 exonic SNPs. Of the exonic SNPs, 1983, located in 1389 genes, are both expressed in the white blood cells and heterozygous in at least one of the 12 individuals, and thus can be examined for differential allelic expression. Of the 1389 genes, 731 (53%) show allele expression differences in at least one individual. To gain insight into the regulatory mechanisms governing allelic expression differences, we analyze a set of 60 genes containing exonic SNPs that are heterozygous in three or more samples, and for which all heterozygotes display differential expression. We find three patterns of allelic expression, suggesting different underlying regulatory mechanisms. Exonic SNPs in three of the 60 genes are monoallelically expressed in the human white blood cells, and when examined in families show expression of only the maternal copy, consistent with regulation by imprinting. Approximately one-third of the genes have the same allele expressed more highly in all heterozygotes, suggesting that their regulation is predominantly influenced by cis-elements in strong linkage disequilibrium with the assayed exonic SNP. The remaining two-thirds of the genes have different alleles expressed more highly in different heterozygotes, suggesting that their expression differences are influenced by factors not in strong linkage disequilibrium with the assayed exonic SNP.

Alleles↗

PubMed2005

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<.01 in tier 1) and 300 genomic control SNPs in 332 matched case-unrelated control pairs. We identified 11 SNPs that were associated with PD (P<.01) in both tier 1 and tier 2 samples and had the same direction of effect. For these SNPs, we combined data from the case-unaffected sibling pair (tier 1) and case-unrelated control pair (tier 2) samples and employed a liberalization of the sibling transmission/disequilibrium test to calculate odds ratios, 95% confidence intervals, and P values. A SNP within the semaphorin 5A gene (SEMA5A) had the lowest combined P value (P=7.62 x 10(-6)). The protein encoded by this gene plays an important role in neurogenesis and in neuronal apoptosis, which is consistent with existing hypotheses regarding PD pathogenesis. A second SNP tagged the PARK11 late-onset PD susceptibility locus (P=1.70 x 10(-5)). In tier 2b, we also selected for genotyping additional SNPs that were borderline significant (P<.05) in tier 1 but that tested a priori biological and genetic hypotheses regarding susceptibility to PD (n=941 SNPs). In analysis of the combined tier 1 and tier 2b data, the two SNPs with the lowest P values (P=9.07 x 10(-6); P=2.96 x 10(-5)) tagged the PARK10 late-onset PD susceptibility locus. Independent replication across populations will clarify the role of the genomic loci tagged by these SNPs in conferring PD susceptibility.

Adult↗

PubMed2005

Fine-scale recombination patterns differ between chimpanzees and humans.

Recombination rates seem to vary extensively along the human genome. Pedigree analysis suggests that rates vary by an order of magnitude when measured at the megabase scale, and at a finer scale, sperm typing studies point to the existence of recombination hotspots. These are short regions (1-2 kb) in which recombination rates are 10-1,000 times higher than the background rate. Less is known about how recombination rates change over time. Here we determined to what degree recombination rates are conserved among closely related species by estimating recombination rates from 14 Mb of linkage disequilibrium data in central chimpanzee and human populations. The results suggest that recombination hotspots are not conserved between the two species and that recombination rates in larger (50 kb) genomic regions are only weakly conserved. Therefore, the recombination landscape has changed markedly between the two species.

Animals↗

PubMed2005

Whole-genome patterns of common DNA variation in three human populations.

Individual differences in DNA sequence are the genetic basis of human variability. We have characterized whole-genome patterns of common human DNA variation by genotyping 1,586,383 single-nucleotide polymorphisms (SNPs) in 71 Americans of European, African, and Asian ancestry. Our results indicate that these SNPs capture most common genetic variation as a result of linkage disequilibrium, the correlation among common SNP alleles. We observe a strong correlation between extended regions of linkage disequilibrium and functional genomic elements. Our data provide a tool for exploring many questions that remain regarding the causal role of common human DNA variation in complex human traits and for investigating the nature of genetic variation within and between human populations.

Black or African American↗

PubMed2004

Matching strategies for genetic association studies in structured populations.

Association studies in populations that are genetically heterogeneous can yield large numbers of spurious associations if population subgroups are unequally represented among cases and controls. This problem is particularly acute for studies involving pooled genotyping of very large numbers of single-nucleotide-polymorphism (SNP) markers, because most methods for analysis of association in structured populations require individual genotyping data. In this study, we present several strategies for matching case and control pools to have similar genetic compositions, based on ancestry information inferred from genotype data for approximately 300 SNPs tiled on an oligonucleotide-based genotyping array. We also discuss methods for measuring the impact of population stratification on an association study. Results for an admixed population and a phenotype strongly confounded with ancestry show that these simple matching strategies can effectively mitigate the impact of population stratification.

Case-Control Studies↗

PubMed2004

Application of pooled genotyping to scan candidate regions for association with HDL cholesterol levels.

Association studies are used to identify genetic determinants of complex human traits of medical interest. With the large number of validated single nucleotide polymorphisms (SNPs) currently available, two limiting factors in association studies are genotyping capability and costs. Pooled DNA genotyping has been proposed as an efficient means of screening SNPs for allele frequency differences in case-control studies and for prioritising them for subsequent individual genotyping analysis. Here, we apply quantitative pooled genotyping followed by individual genotyping and replication to identify associations with human serum high-density lipoprotein (HDL) cholesterol levels. The DNA from individuals with low and high HDL cholesterol levels was pooled separately, each pool was amplified by polymerase chain reaction in triplicate and each amplified product was separately hybridised to a high-density oligonucleotide array. Allele frequency differences between case and control groups with low and high HDL cholesterol levels were estimated for 7,283 SNPs distributed across 71 candidate gene regions spanning a total of 17.1 megabases. A novel method was developed to take advantage of independently derived haplotype map information to improve the pooled estimates of allele frequency differences. A subset of SNPs with the largest estimated allele frequency differences between low and high HDL cholesterol groups was chosen for individual genotyping in the study population, as well as in a separate replication population. Four SNPs in a single haplotype block within the cholesteryl ester transfer protein (CETP) gene interval were significantly associated with HDL cholesterol levels in both populations. Our study is among the first to demonstrate the application of pooled genotyping followed by confirmation with individual genotyping to identify genetic determinants of a complex trait.

Case-Control Studies↗

PubMed2002

Three new human members of the lipid transfer/lipopolysaccharide binding protein family (LT/LBP).

We have identified three novel, rarely expressed human genes that encode new members of the lipid transfer/lipopolysaccharide binding protein (LT/LBP) gene family based on sequence homology. BPI and other members of the LT/LBP family are structurally related proteins capable of binding phospholipids and lipopolysaccharides. Real-time PCR studies indicate that BPIL1 and BPIL3 are highly expressed in hypertrophic tonsils. In situ hybridization analysis of BPIL2 shows prominent expression in skin specimens from psoriasis patients. BPIL1 and BPIL3 map to Chromosome 20q11; thus, these novel genes form a cluster with BPI and two other members of the LT/LBP gene family on the long arm of human Chr 20. BPIL2maps to Chr 22q13. The exon/intron organization of all three genes is highly conserved with that of BPI, suggesting evolution from a common ancestor.

Amino Acid Sequence↗

PubMed2002

A genome scan for loci influencing anti-atherogenic serum bilirubin levels.

Epidemiological studies have shown an association of decreased serum bilirubin levels with coronary artery disease. Two segregation analyses in large pedigrees have suggested a major gene responsible for high bilirubin levels occurring in about 12% of the population. Based on a recessive model from a previous segregation analysis, we performed a genome scan using 587 markers genotyped in 862 individuals from 48 Utah pedigrees to detect loci linked to high bilirubin levels. As a complementary approach, non-parametric linkage (NPL) analysis was performed. These two methods identified four regions showing evidence for linkage. The first region is on chromosome 2q34-37 with multipoint LOD and NPL scores of 3.01 and 3.22, respectively, for marker D2S1363. This region contains a previously described gene, uridine diphosphate glycosyltransferase 1, which has been associated with high bilirubin levels. A polymorphism in the promoter of this gene was recently shown to be responsible for Gilbert syndrome which is associated with mild hyperbilirubinemia. The other regions were found on chromosomes 9q21, 10q25-26, and 18q12 with maximum NPL scores of 2.39, 1.55, and 2.79, respectively. Furthermore, we investigated in these pedigrees the association between bilirubin levels and coronary artery disease. One-hundred and sixty-one male and 41 female subjects had already suffered a coronary artery disease event. Male patients showed significantly lower bilirubin concentrations than age-matched controls. This association, however, was not observed in females. These results provide evidence that loci influencing bilirubin variation exist on chromosomes 2q34-37, 9q21, 10q25-26, and 18q12 and confirms the association of low bilirubin levels with coronary artery disease in males.

Adult↗