Biomedical subjects

T H Beaty

Publications and source records attributed to T H Beaty.

At least 19 recordsLinked to original sources

PubMed2006

Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations.

Isolated oral clefts, including cleft lip with/without cleft palate (CL/P) and cleft palate (CP), have a complex and heterogeneous etiology. Case-parent trios from three populations were used to study genes spanning chromosome 2, where single nucleotide polymorphic (SNP) markers were analyzed individually and as haplotypes. Case-parent trios from three populations (74 from Maryland, 64 from Singapore and 95 from Taiwan) were genotyped for 962 SNPs in 104 genes on chromosome 2, including two well-recognized candidate genes: TGFA and SATB2. Individual SNPs and haplotypes (in sliding windows of 2-5 SNPs) were used to test for linkage and disequilibrium separately in CL/P and CP trios. A novel candidate gene (ZNF533) showed consistent evidence of linkage and disequilibrium in all three populations for both CL/P and CP. SNPs in key regions of ZNF533 showed considerable variability in estimated genotypic odds ratios and their significance, suggesting allelic heterogeneity. Haplotype frequencies for regions of ZNF533 were estimated and used to partition genetic variance into among-and within-population components. Wright's fixation index, a measure of genetic diversity, showed little difference between Singapore and Taiwan compared with Maryland. The tensin-1 gene (TNS1) also showed evidence of linkage and disequilibrium among both CL/P and CP trios in all three populations, albeit at a lower level of significance. Additional genes (VAX2, GLI2, ZHFX1B on 2p; WNT6-WNT10A and COL4A3-COL4A4 on 2q) showed consistent evidence of linkage and disequilibrium only among CL/P trios in all three populations, and TGFA showed significant evidence in two of three populations.

Chromosome Mapping↗

PubMed2006

High throughput SNP and expression analyses of candidate genes for non-syndromic oral clefts.

BACKGROUND: Recent work suggests that multiple genes and several environmental risk factors influence risk for non-syndromic oral clefts, one of the most common birth defects in humans. Advances in high-throughput genotyping technology now make it possible to test multiple markers in many candidate genes simultaneously. METHODS: We present findings from family based association tests of single nucleotide polymorphism (SNP) markers in 64 candidate genes genotyped using the BeadArray approach in 58 case-parent trios from Maryland (USA) to illustrate how multiple markers in multiple genes can be analysed. To assess whether these genes were expressed in human craniofacial structures relevant to palate and lip development, we also analysed data from the Craniofacial and Oral Gene Expression Network (COGENE) consortium, and searched public databases for expression profiles of these genes. RESULTS: Thirteen candidate genes showed significant evidence of linkage in the presence of disequilibrium, and ten of these were found to be expressed in relevant embryonic tissues: SP100, MLPH, HDAC4, LEF1, C6orf105, CD44, ALX4, ZNF202, CRHR1, and MAPT. Three other genes showing statistical evidence (ADH1C, SCN3B, and IMP5) were not expressed in the embryonic tissues examined here. CONCLUSIONS: This approach demonstrates how statistical evidence on large numbers of SNP markers typed in case-parent trios can be combined with expression data to identify candidate genes for complex disorders. Many of the genes reported here have not been previously studied as candidates for oral clefts and warrant further investigation.

Chromosome Mapping↗

PubMed2006

Variants in the gene encoding C3 are associated with asthma and related phenotypes among African Caribbean families.

Proinflammatory and immunoregulatory products from C3 play a major role in phagocytosis, respiratory burst, and airways inflammation. C3 is critical in adaptive immunity; studies in mice deficient in C3 demonstrate that features of asthma are significantly attenuated in the absence of C3. To test the hypothesis that the C3 gene on chromosome 19p13.3-p13.2 contains variants associated with asthma and related phenotypes, we genotyped 25 single nucleotide polymorphism (SNP) markers distributed at intervals of approximately 1.9 kb within the C3 gene in 852 African Caribbean subjects from 125 nuclear and extended pedigrees. We used the multiallelic test in the family-based association test program to examine sliding windows comprised of 2-6 SNPs. A five-SNP window between markers rs10402876 and rs366510 provided strongest evidence for linkage in the presence of linkage disequilibrium for asthma, high log[total IgE], and high log[IL-13]/[log[IFN-gamma] in terms of global P-values (P = 0.00027, 0.00013, and 0.003, respectively). A three-SNP haplotype GGC for the first three of these markers showed best overall significance for the three phenotypes (P = 0.003, 0.007, 0.018, respectively) considering haplotype-specific tests. Taken together, these results implicate the C3 gene as a priority candidate controlling risk for asthma and allergic disease in this population of African descent.

Asthma↗

PubMed2005

Haplotype diversity in 11 candidate genes across four populations.

Analysis of haplotypes based on multiple single-nucleotide polymorphisms (SNP) is becoming common for both candidate gene and fine-mapping studies. Before embarking on studies of haplotypes from genetically distinct populations, however, it is important to consider variation both in linkage disequilibrium (LD) and in haplotype frequencies within and across populations, as both vary. Such diversity will influence the choice of "tagging" SNPs for candidate gene or whole-genome association studies because some markers will not be polymorphic in all samples and some haplotypes will be poorly represented or completely absent. Here we analyze 11 genes, originally chosen as candidate genes for oral clefts, where multiple markers were genotyped on individuals from four populations. Estimated haplotype frequencies, measures of pairwise LD, and genetic diversity were computed for 135 European-Americans, 57 Chinese-Singaporeans, 45 Malay-Singaporeans, and 46 Indian-Singaporeans. Patterns of pairwise LD were compared across these four populations and haplotype frequencies were used to assess genetic variation. Although these populations are fairly similar in allele frequencies and overall patterns of LD, both haplotype frequencies and genetic diversity varied significantly across populations. Such haplotype diversity has implications for designing studies of association involving samples from genetically distinct populations.

Analysis of Variance↗

PubMed2004

Genome scan for loci linked to mite sensitivity: the Collaborative Study on the Genetics of Asthma (CSGA).

Mite sensitivity has been reported to be a major risk factor for asthma. As part of the Collaborative Study on the Genetics of Asthma (CSGA), a genome scan using mite reactivity (Dermatophagoides Pteronyssinus (Der p) and Dermatophagoides farinae (Der f)) as the phenotype was conducted. In 287 CSGA families, 122 were informative for linkage. Evidence supporting linkage was observed for regions on chromosome 19 (D19S591, lod=2.43, P=0.0008; D19S1037, lod=1.57, P=0.007) and chromosome 20 (D20S473/D20S604, lod=1.41, P=0.01). All three ethnic groups appeared to contribute to the evidence for linkage on chromosome 20. African-American families gave strongest support for linkage on chromosomes 3 (D3S2409, lod=1.33, P=0.01), 12 (D12S373, lod=1.51, P=0.008) and 18 (ATA82B02, lod=1.32, P=0.01). Caucasian families showed strong evidence for linkage on chromosome 19 (D19S591, lod=3.51, P=0.00006). Hispanic families supported linkage on chromosomes 11 (D11S1984, lod=1.56, P=0.007), 13 (D13S787, lod=1.30, P=0.01) and 20 (D20S470, lod=1.71, P=0.005). These results suggest that multiple genes may be involved in controlling skin reactivity to Dermatophoigoies.

Animals↗

PubMed2003

Genetic influence of CXCR6 chemokine receptor alleles on PCP-mediated AIDS progression among African Americans.

CXCR6 is a chemokine receptor and the primary coreceptor in SIV infection. A single nucleotide polymorphism 1469G-->A, results in a nonconservative change in codon 3 (CXCR6-E3K) of the N-terminus of the coreceptor. To investigate the relation between the chemokine receptor CXCR6 genotype and progression to Pneumocystis carinii pneumonia (PCP) and from PCP to death, we clinically assessed and genotyped 805 individuals from an African-American injection drug-using cohort in Baltimore, MD, USA, for this CXCR6-E3K polymorphism. The allele frequency of CXCR6-3K was high (44%) in African Americans and rare in European Americans (f<1%). Although time to AIDS and PCP was similar for all CXCR6 genotypes, the median survival time from PCP to death for the CXCR6-3E/E and CXCR6-3E/K genotype was 1.5 years compared to 3.1 years for the CXCR6-K/K genotype. Individuals homozygous or heterozygous for the CXCR6-3E allele were 5.6 times more likely to die a PCP-mediated AIDS-related death than were individuals homozygous for CXCR6-3K. This study shows an association between CXCR6 genotype and progression from PCP to death among African-Americans with HIV. We suggest that CXCR6 may play a role in late-stage HIV-1 infection and may alter the progression to death after initial infection with PCP.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Genome-wide scan of bipolar disorder in 65 pedigrees: supportive evidence for linkage at 8q24, 18q22, 4q32, 2p12, and 13q12.

The purpose of this study was to assess 65 pedigrees ascertained through a Bipolar I (BPI) proband for evidence of linkage, using nonparametric methods in a genome-wide scan and for possible parent of origin effect using several analytical methods. We identified 15 loci with nominally significant evidence for increased allele sharing among affected relative pairs. Eight of these regions, at 8q24, 18q22, 4q32, 13q12, 4q35, 10q26, 2p12, and 12q24, directly overlap with previously reported evidence of linkage to bipolar disorder. Five regions at 20p13, 2p22, 14q23, 9p13, and 1q41 are within several Mb of previously reported regions. We report our findings in rank order and the top five markers had an NPL>2.5. The peak finding in these regions were D8S256 at 8q24, NPL 3.13; D18S878 at 18q22, NPL 2.90; D4S1629 at 4q32, NPL 2.80; D2S99 at 2p12, NPL 2.54; and D13S1493 at 13q12, NPL 2.53. No locus produced statistically significant evidence for linkage at the genome-wide level. The parent of origin effect was studied and consistent with our previous findings, evidence for a locus on 18q22 was predominantly from families wherein the father or paternal lineage was affected. There was evidence consistent with paternal imprinting at the loci on 13q12 and 1q41.

Adolescent↗

PubMed2002

Segregation analysis of waist circumference, hip circumference and waist-to-hip ratio in the Korean Nationwide Family Study.

AIM: A central distribution of adipose tissue is frequently associated with cardiovascular disease and its risk factors. In this study, we investigated environmental, familial and genetic influences on waist circumference (WC), hip circumference (HC) and waist-to-hip ratio (WHR) in 2507 members of 435 families who had participated in the Korean Nationwide Health Examination Survey. METHOD: Maximum likelihood methods were used to fit several genetic and nongenetic models of inheritance to these data to determine whether an unobserved Mendelian major gene could explain the familial distribution of WC, HC and WHR. Adjustments for age, age(2), body mass index, smoking, alcohol consumption and exercise were carried out separately for males and females by multiple regression procedures for WC, HC and WHR phenotypes prior to segregation analysis. Regression models were used to test genetic and non-genetic models in these 435 families. RESULTS: Segregation analysis did not provide statistical evidence of a major gene controlling either HC or WHR. Mendelian single-locus models with two underlying genotypic distributions were best supported by these data on WC, and this putative major gene explained the 22.4% of variance in adjusted WC. CONCLUSION: Future linkage studies may be worthwhile to further clarify the mechanisms controlling WC.

Adipose Tissue↗

PubMed2002

Genetic contribution to factor VII levels in families of patients undergoing coronary arteriography.

An elevated plasma level of factor VII is a risk factor for coronary artery disease. We investigated environmental, familial, and genetic influences on factor VII activity in 508 family members of 87 probands who underwent elective coronary arteriography. Maximum likelihood methods were used to fit several genetic and non-genetic models of inheritance to these data to determine whether an unobserved Mendelian major gene could explain the familial distribution of factor VII. Factor VII activities were adjusted for age, gender, body mass index, smoking, alcohol consumption, menopause status, and triglycerides prior to this segregation analysis (this model accounted for 33.5% of the total variation). Adjusted factor VII activities showed strong familial aggregation with an estimated parent-offspring correlation of 0.34, sibling correlation of 0.36 and a smaller spouse correlation of 0.16. Regressive models were used to test genetic and non-genetic models in these 87 families. Mendelian single-locus models with either two or three underlying genotypic distributions of factor VII activities were best supported by these data. Essentially, these Mendelian models suggest most individuals come from a low distribution (mean, 116%), with a few individuals homozygous for a high allele drawn from a distribution with a mean of 166%. Future linkage studies may be worthwhile to further clarify the mechanisms controlling factor VII activity.

Adolescent↗

PubMed2001

Genomewide screen and identification of gene-gene interactions for asthma-susceptibility loci in three U.S. populations: collaborative study on the genetics of asthma.

The genomewide screen to search for asthma-susceptibility loci, in the Collaborative Study on the Genetics of Asthma (CSGA), has been conducted in two stages and includes 266 families (199 nuclear and 67 extended pedigrees) from three U.S. populations: African American, European American, and Hispanic. Evidence for linkage with the asthma phenotype was observed for multiple chromosomal regions, through use of several analytical approaches that facilitated the identification of multiple disease loci. Ethnicity-specific analyses, which allowed for different frequencies of asthma-susceptibility genes in each ethnic population, provided the strongest evidence for linkage at 6p21 in the European American population, at 11q21 in the African American population, and at 1p32 in the Hispanic population. Both the conditional analysis and the affected-sib-pair two-locus analysis provided further evidence for linkage, at 5q31, 8p23, 12q22, and 15q13. Several of these regions have been observed in other genomewide screens and linkage or association studies, for asthma and related phenotypes. These results were used to develop a conceptual model to delineate asthma-susceptibility loci and their genetic interactions, which provides a promising basis for initiation of fine-mapping studies and, ultimately, for gene identification.

Adolescent↗

PubMed2001

Multipoint linkage-disequilibrium-mapping approach based on the case-parent trio design.

In the present study we propose a multipoint approach, for the mapping of genes, that is based on the case-parent trio design. We first derive an expression for the expected preferential-allele-transmission statistics for transmission, from either parent to an affected child, for an arbitrary location within a chromosomal region demarcated by several genetic markers. No assumption about genetic mechanism is needed in this derivation, beyond the assumption that no more than one disease gene lies in the region framed by the markers. When one builds on this representation, the way in which one may maximize the genetic information from multiple markers becomes obvious. This proposed method differs from the popular transmission/disequilibrium test (TDT) approach for fine mapping, in the following ways: First, in contrast with the TDT approach, all markers contribute information, regardless of whether the parents are heterozygous at any one marker, and incomplete trio data can be utilized in our approach. Second, rather than performing the TDT at each marker separately, we propose a single test statistic that follows a chi(2) distribution with 1 df, under the null hypothesis of no linkage or linkage disequilibrium to the region. Third, in the presence of linkage evidence, we offer a means to estimate the location of the disease locus along with its sampling uncertainty. We illustrate the proposed method with data from a family study of asthma, conducted in Barbados.

Alleles↗

PubMed2001

Testing for gene-gene interaction controlling total IgE in families from Barbados: evidence of sensitivity regarding linkage heterogeneity among families.

Genetic heterogeneity has been proposed as a hallmark feature of allergic disease. To test the hypothesis that total IgE levels are jointly influenced by a locus on chromosome 12q21.1-q21.31 and a locus on 17q11.2-q21.2, we conducted multipoint allele-sharing analyses using nonparametric linkage (NPL) methods on Afro-Caribbean families from Barbados to test for evidence of gene-gene interactions. Significant correlations were observed between NPL scores at D12S1052 and both D17S1293 and D17S1299 for a dichotomized phenotype of total IgE. An analysis of family-specific NPL scores revealed that evidence for interaction was being driven largely by one multiplex pedigree (NPL = 12.01, 12.23, and 12.16 at D12S1052, D17S1293, and D17S1299, respectively). Using the programs SIMWALK (v2.0) and GOLD, a different set of haplotypes in this influential family was observed around D12S1052 and the 17q loci compared to the other Barbados pedigrees. Our findings are a classic example of founder effect, provide evidence for sensitivity of this type of linkage analysis to unusual pedigrees, and highlight an element of genetic heterogeneity that has been given little attention in the study of complex traits.

Asthma↗

PubMed2001

Multipoint analysis using affected sib pairs: incorporating linkage evidence from unlinked regions.

In this paper, we proposed a multipoint method to assess evidence of linkage to one region by incorporating linkage evidence from another region. This approach uses affected sib pairs in which the number of alleles shared identical by descent (IBD) is the primary statistic. This generalized estimating equation (GEE) approach is robust in that no assumption about the mode of inheritance is required, other than assuming the two regions being considered are unlinked and that there is no more than one susceptibility gene in each region. The method proposed here uses data from all available families to simultaneously test the hypothesis of statistical interaction between regions and to estimate the location of the susceptibility gene in the target region. As an illustration, we have applied this GEE method to an asthma sib pair study (Wjst et al. [1999] Genomics 58:1-8), which earlier reported evidence of linkage to chromosome 6 but showed no evidence for chromosome 20. Our results yield strong evidence to chromosome 20 (P value = 0.0001) after incorporating linkage information from chromosome 6. Furthermore, it estimates with 95% certainty that the map location of the susceptibility gene is flanked by markers D20S186 and D20S101, which are approximately 16.3 cM apart.

Asthma↗

PubMed2001

Multilocus linkage analysis of the German asthma data.

We analyzed data from the German Asthma Genetics Group with three methods that utilize pedigree-specific nonparametric linkage scores to facilitate the search for multiple independent and interacting susceptibility loci. The three methods included a conditional analysis, logistic regression, and neural networks. Although there were differences, the three methods identified many of the same susceptibility loci. The most consistent evidence was provided for loci on chromosomes 1, 2, 6, 9, and 15. Both the conditional and the logistic regression analyses suggested an epistatic relationship between loci on chromosomes 2 and 9. The logistic regression analysis further revealed evidence for locus heterogeneity between loci on chromosomes 6 and 15. Finally, the neural network analysis identified a potential locus on chromosome 17 that was not identified in the other analyses.

Adult↗

PubMed2001

Multipoint linkage analysis under heterogeneity: incorporation of parametric and nonparametric approaches.

Using a recently developed multipoint parametric method, which tests for linkage in the presence of heterogeneity, we performed a genome-wide search for linkage using the German asthma data. Both dominant and recessive models were assumed in this parametric approach. Identity-by-descent (IBD) sharing for affected sibs was also calculated to help identify an appropriate genetic model and localize the trait locus. The strongest evidence for linkage was on chromosome 6 (p-value = 0.00006) under the dominant model with heterogeneity. Using both linkage and IBD sharing information for D6S422 (36.55 cM) on chromosome 6, we conducted exploratory analyses to locate additional trait loci that might explain the linkage heterogeneity. We found evidence of heterogeneity between D6S422 and D11S4111 based on a test of association (p-value = 0.0015).

Adult↗

PubMed2001

Genome-wide linkage analyses of total serum IgE using variance components analysis in asthmatic families.

Variance components models were used to analyze total IgE levels in families ascertained though the Collaborative Study of the Genetics of Asthma (CSGA) using a genome-wide array of polymorphic markers. While IgE levels are known to be associated with clinical asthma and recognized to be under strong genetic control (here the heritability was estimated at 44-60% in the three racial groups), specific genes influencing this trait are still largely unknown. Multipoint analysis of 323 markers yielded little indication of specific regions containing a trait locus controlling total serum IgE levels (adjusted for age and gender). Although a number of regions showed LOD statistics above 1.5 in Caucasian families (chromosome 4) and in African-American families (chromosomes 2 and 4), none yielded consistent evidence in all three racial groups. Analysis of total IgE adjusted for gender, age and Allergy Index (a quantitative score of skin test sensitivity to 14 common aeroallergens) was conducted on these data. In this analysis, a much stronger signal for a trait locus controlling adjusted log[total IgE] was seen on the telomeric end of chromosome 18, but only in Caucasian families. This region accounted for most of the genetic variation in log[total IgE], and may represent a quantitative trait locus for IgE levels independent of atopic response. Oligogenic analysis accounting simultaneously for the contribution of this locus on chromosome 18 and other chromosomal regions showing some evidence of linkage in these Caucasian families (on chromosomes 2, 4 and 20) failed to yield significant evidence for interaction.

Asthma↗

PubMed2001

Autosomal dominant inheritance of prostate cancer: a confirmatory study.

OBJECTIVES: To confirm, in a study of a large, independent cohort of families with prostate cancer, the findings of three segregation analyses that have suggested the existence of an inherited form of prostate cancer with an autosomal dominant inheritance mode. METHODS: Between January 1991 and December 1993, 1199 pedigrees were ascertained through single, unrelated, prostate cancer probands who presented for radical prostatectomy at the Division of Urologic Surgery, Washington University Medical Center in St. Louis, Missouri. Maximum likelihood segregation analysis was used to test specifically for mendelian inheritance of prostate cancer. RESULTS: Segregation analyses revealed that the familial aggregation of prostate cancer can be best explained by the autosomal dominant inheritance of a rare (q = 0.0037) high-risk allele. According to the best-fitting autosomal dominant model, 97% of all carriers will be affected by 85 years of age compared with 10% of noncarriers. Furthermore, the autosomal dominant model predicts that the high-risk allele accounts for a large proportion (65%) of all patients diagnosed with prostate cancer before 56 years of age. However, of all prostate cancer cases, a relatively small proportion is inherited (8% by 85 years old). CONCLUSIONS: These results are in agreement with earlier reports of segregation analyses of prostate cancer and strengthen the evidence that prostate cancer is inherited in a mendelian fashion within a subset of families.

Age Factors↗

PubMed2001

A case-control study of nonsyndromic oral clefts in Maryland.

PURPOSE: Isolated, nonsyndromic oral clefts cases (n = 171) and unaffected controls (n = 182) were used to identify both genetic and environmental risk factors. METHODS: Infants born in Maryland between 1992 to 1998 with an isolated, nonsyndromic oral cleft [cleft lip (CL), cleft lip and palate (CLP), or cleft palate (CP)] were recruited and exposure plus family history data were collected. Controls were unaffected infants. DNA was collected from all cases and their parents, plus controls. RESULTS: No statistically significant association was found between any of the following: maternal smoking, vitamin use, urinary tract infection, or recreational drug use in either univariate analysis or after adjusting for maternal age and education. More control mothers reported alcohol use during the critical time period of pregnancy (one month before conception through the first trimester) as compared to case mothers. There was a 10-fold increase in risk to siblings of cases as compared to siblings of controls. Markers at four candidate genes were examined: transforming growth factor alpha (TGF alpha), transforming growth factor beta 3 (TGF beta 3), MSX1, and BCL3. Only MSX1 showed significant differences in allele frequencies between CP cases and controls. MSX1 also showed significant evidence of linkage disequilibrium with a susceptibility gene controlling risk for CP. CONCLUSION: Most environmental risk factors examined here gave little evidence of association with risk to isolated, nonsyndromic oral clefts, although any alcohol consumption seemed protective. MSX1 showed evidence of linkage disequilibrium in both case-control and case-parent trio analysis.

Case-Control Studies↗