Genome-wide linkage analysis of age at onset of alcohol dependence: a comparison between microsatellites and single-nucleotide polymorphisms

BACKGROUND: Using the dataset provided for Genetic Analysis Workshop 14 by the Collaborative Study on the Genetics of Alcoholism, we performed genome-wide linkage analysis of age at onset of alcoholism to compare the utility of microsatellites and single-nucleotide polymorphisms (SNPs) in genetic linkage study. METHODS: A multipoint nonparametric variance component linkage analysis method was applied to the survival distribution function obtained from semiparametric proportional hazards model of the age at onset phenotype of alcoholism. Three separate linkage analyses were carried out using 315 microsatellites, 2,467 and 9,467 SNPs, spanning the 22 autosomal chromosomes. RESULTS: Heritability of age at onset was estimated to be approximately 12% (p < 0.001). We observed weak correlation, both in trend and strength, of genome-wide linkage signals between microsatellites and SNPs. Results from SNPs revealed more and stronger linkage signals across the genome compared with those from microsatellites. The only suggestive evidence of linkage from microsatellites was on chromosome 1 (LOD of 1.43). Differences in map densities between the two sets of SNPs used in this study did not appear to confer an advantage in terms of strength of linkage signals. CONCLUSION: Our study provided support for better performance of dense SNP maps compared with the sparse mirosatellite maps currently available for linkage analysis of quantitative traits. This better performance could be attributable to precise definition and high map resolutions achievable with dense SNP maps, thus resulting in increased power to detect possible loci affecting given trait or disease

Use of supplementary phenotype to identify additional rheumatoid arthritis loci in a linkage analysis of 342 UK affected sibling pair families

<p>Abstract</p> <p>Background</p> <p>Although rheumatoid arthritis has been shown to have moderately strong genetic component, both linked loci identified in linkage analyses and susceptibility variants from association studies are short of adequately accounting for a comprehensive catalogue of the molecular factors underlying this complex disease. The objective of this study was to use supplementary phenotype based on cumulative hazard of rheumatoid arthritis to identify linkage evidence for new and additional rheumatoid arthritis loci in a genome-wide linkage analysis of 342 affected sibling pair families from the United Kingdom.</p> <p>Methods</p> <p>Using proportional hazards model, we estimated cumulative hazard of rheumatoid arthritis and then used it as a quantitative trait in a non-parametric multipoint variance component linkage analysis with 353 microsatellite markers distributed across the 22 autosomal chromosomes.</p> <p>Results</p> <p>We identified 3 new loci with genome-wide suggestive linkage evidence for rheumatoid arthritis on 9q21.13, 15p11.1 and 20q13.33. Our results also confirmed previously reported linkage evidence in the HLA-DRB1 region on chromosome 6 and on locus 1q32.1.</p> <p>Conclusion</p> <p>This study demonstrates the potential for information gain through the use of supplementary phenotypes in genetic study of complex diseases to identify new and additional potential linked loci that are not detected by linkage analysis of traditional phenotypes; and our results provide further evidence of the involvement of multiple loci in the genetic aetiology of rheumatoid arthritis.</p

Prevalence of ECG abnormalities among adults with metabolic syndrome in a Nigerian Teaching Hospital

Background: Co-existence of metabolic syndrome (MetS) and electrocardiography (ECG) abnormalities heightens the risk of sudden cardiac death. However, there is a gap in evidence of how ECG changes cluster among continental Africans with or without MetS. Methods: We included 491 participants with interpretable ECG tracings who were consecutively recruited into the Cardiovascular Risk Prediction Registry (CRP). CRP is a registry of newly presenting patients into cardiology clinic of the University College Hospital, Nigeria, with a main objective of cardiovascular risk stratification to prevent cardiovascular morbidity and mortality. Using the International Diabetic Federation (IDF) criteria they were divided into those with metabolic syndrome and non-metabolic syndrome. Results: Four hundred and ninety-one participants comprising 48.3% women with mean age 53.72\ub115.2 years who met the IDF criteria with complete ECG interpretations were analyzed with 44.2% (men 38.6%; women 50.2%) of the participants having MetS while 74% had ECG abnormalities. Compared to women, men had higher mean serum total cholesterol, creatinine, smoking, and alcohol use, family history of hypertension and diabetes mellitus, QT prolongation, LVH plus or minus strain pattern, and ECG abnormalities in general. Women were heavier, had higher heart rate and proportions of MetS. ECG findings among those with or without MetS were not significantly different. In men, IDF metabolic score was associated with conduction abnormalities (p=0.039) and combined ECG abnormality (p=0.042) which became more significant with an exclusion of QT prolongation (p=0.004). Also, IDF abdominal obesity was associated with QT prolongation (p=0.017), combined ECG abnormality (p=0.034) while HDLc correlated with ECG abnormalities (0.037) in men. There was no significant associations of components of metabolic syndrome with ECG abnormalities among women. Conclusion: There was a high prevalence of MetS and abnormal ECG among the studied population. Abnormal ECG findings were more common in men with no differential association in people with or without MetS. However, a significant association existed between certain components of MetS and ECG abnormalities in men only. Male gender and HDLc were independent predictors of ECG Abnormalities

Control procedures and estimators of the false discovery rate and their application in low-dimensional settings: an empirical investigation

Background: When many (up to millions) of statistical tests are conducted in discovery set analyses such as genome-wide association studies (GWAS), approaches controlling family-wise error rate (FWER) or false discovery rate (FDR) are required to reduce the number of false positive decisions. Some methods were specifically developed in the context of high-dimensional settings and partially rely on the estimation of the proportion of true null hypotheses. However, these approaches are also applied in low-dimensional settings such as replication set analyses that might be restricted to a small number of specific hypotheses. The aim of this study was to compare different approaches in low-dimensional settings using (a) real data from the CKDGen Consortium and (b) a simulation study. Results: In both application and simulation FWER approaches were less powerful compared to FDR control methods, whether a larger number of hypotheses were tested or not. Most powerful was the q-value method. However, the specificity of this method to maintain true null hypotheses was especially decreased when the number of tested hypotheses was small. In this low-dimensional situation, estimation of the proportion of true null hypotheses was biased. Conclusions: The results highlight the importance of a sizeable data set for a reliable estimation of the proportion of true null hypotheses. Consequently, methods relying on this estimation should only be applied in high-dimensional settings. Furthermore, if the focus lies on testing of a small number of hypotheses such as in replication settings, FWER methods rather than FDR methods should be preferred to maintain high specificity

Association of variants at BCL11A and HBS1L-MYB with hemoglobin F and hospitalization rates among sickle cell patients in Cameroon

BACKGROUND: Genetic variation at loci influencing adult levels of HbF have been shown to modify the clinical course of sickle cell disease (SCD). Data on this important aspect of SCD have not yet been reported from West Africa. We investigated the relationship between HbF levels and the relevant genetic loci in 610 patients with SCD (98% HbSS homozygotes) from Cameroon, and compared the results to a well-characterized African-American cohort. Methods and FINDINGS: Socio-demographic and clinical features were collected and medical records reviewed. Only patients >5 years old, who had not received a blood transfusion or treatment with hydroxyurea were included. Hemoglobin electrophoresis and a full blood count were conducted upon arrival at the hospital. RFLP-PCR was used to describe the HBB gene haplotypes. SNaPshot PCR, Capillary electrophoresis and cycle sequencing were used for the genotyping of 10 selected SNPs. Genetic analysis was performed with PLINK software and statistical models in the statistical package R. Allele frequencies of relevant variants at BCL11A were similar to those detected in African Americans; although the relationships with Hb F were significant (p <.001), they explained substantially less of the variance in HbF than was observed among African Americans (∼ 2% vs 10%). SNPs in HBS1L-MYB region ( HMIP ) likewise had a significant impact on HbF, however, we did not find an association between HbF and the variations in HBB cluster and OR51B5/6 locus on chromosome 11p, due in part to the virtual absence of the Senegal and Indian Arab haplotypes. We also found evidence that selected SNPs in HBS1L-MYB region ( HMIP ) and BCL11A affect both other hematological indices and rates of hospitalization. CONCLUSIONS: This study has confirmed the associations of SNPs in BCL11A and HBS1L-MYB and fetal haemoglobin in Cameroonian SCA patients; hematological indices and hospitalization rates were also associated with specific allelic variants

Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P \u3c 1.25×10−8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension

Where\u27s the Kale? Environmental Availability of Fruits and Vegetables in Two Racially Dissimilar Communities

Minority communities across the United States have limited numbers of stores that offer a variety of fruits and vegetables, creating major barriers to good eating habits and nutritional practices among minority groups such as African Americans. Factors like environmental availability of healthy food options have not been fully investigated as possible sources of current cross-population differences in disease. The present study examined whether a predominantly African American neighborhood had disproportionately less availability of fruits and vegetables than a predominantly non-Hispanic White neighborhood. Availability was judged on the bases of the types of stores available in each community and the specific types of fruits and vegetables made available in each store. The availability of fruits and vegetables in the food stores of each community was assessed by physically canvassing neighborhood food stores and taking a census of available fruit and vegetable items based on a a list of fruits and vegetables derived from the DASH diet. The predominantly African American community under study had fewer varieties of fresh fruits and vegetables and fewer stores offering larger varieties of fruits and vegetables. Reduced choice to purchase fruits and vegetables among minority populations potentially increases health disparities. Improving local food environments is one important strategy to increase access to a healthy diet in minority communities

Complex Segregation Analysis of Pedigrees from the Gilda Radner Familial Ovarian Cancer Registry Reveals Evidence for Mendelian Dominant Inheritance

Familial component is estimated to account for about 10% of ovarian cancer. However, the mode of inheritance of ovarian cancer remains poorly understood. The goal of this study was to investigate the inheritance model that best fits the observed transmission pattern of ovarian cancer among 7669 members of 1919 pedigrees ascertained through probands from the Gilda Radner Familial Ovarian Cancer Registry at Roswell Park Cancer Institute, Buffalo, New York.Using the Statistical Analysis for Genetic Epidemiology program, we carried out complex segregation analyses of ovarian cancer affection status by fitting different genetic hypothesis-based regressive multivariate logistic models. We evaluated the likelihood of sporadic, major gene, environmental, general, and six types of Mendelian models. Under each hypothesized model, we also estimated the susceptibility allele frequency, transmission probabilities for the susceptibility allele, baseline susceptibility and estimates of familial association. Comparisons between models were carried out using either maximum likelihood ratio test in the case of hierarchical models, or Akaike information criterion for non-nested models. When assessed against sporadic model without familial association, the model with both parent-offspring and sib-sib residual association could not be rejected. Likewise, the Mendelian dominant model that included familial residual association provided the best-fitting for the inheritance of ovarian cancer. The estimated disease allele frequency in the dominant model was 0.21.This report provides support for a genetic role in susceptibility to ovarian cancer with a major autosomal dominant component. This model does not preclude the possibility of polygenic inheritance of combined effects of multiple low penetrance susceptibility alleles segregating dominantly

Genome‐wide survey in African Americans demonstrates potential epistasis of fitness in the human genome

The role played by epistasis between alleles at unlinked loci in shaping population fitness has been debated for many years and the existing evidence has been mainly accumulated from model organisms. In model organisms, fitness epistasis can be systematically inferred by detecting nonindependence of genotypic values between loci in a population and confirmed through examining the number of offspring produced in two‐locus genotype groups. No systematic study has been conducted to detect epistasis of fitness in humans owing to experimental constraints. In this study, we developed a novel method to detect fitness epistasis by testing the correlation between local ancestries on different chromosomes in an admixed population. We inferred local ancestry across the genome in 16,252 unrelated African Americans and systematically examined the pairwise correlations between the genomic regions on different chromosomes. Our analysis revealed a pair of genomic regions on chromosomes 4 and 6 that show significant local ancestry correlation (P‐value = 4.01 × 10−8) that can be potentially attributed to fitness epistasis. However, we also observed substantial local ancestry correlation that cannot be explained by systemic ancestry inference bias. To our knowledge, this study is the first to systematically examine evidence of fitness epistasis across the human genome.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135958/1/gepi22026.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135958/2/gepi22026_am.pd

Genetic Background of Patients from a University Medical Center in Manhattan: Implications for Personalized Medicine

Background: The rapid progress currently being made in genomic science has created interest in potential clinical applications; however, formal translational research has been limited thus far. Studies of population genetics have demonstrated substantial variation in allele frequencies and haplotype structure at loci of medical relevance and the genetic background of patient cohorts may often be complex. Methods and Findings: To describe the heterogeneity in an unselected clinical sample we used the Affymetrix 6.0 gene array chip to genotype self-identified European Americans (N = 326), African Americans (N = 324) and Hispanics (N = 327) from the medical practice of Mount Sinai Medical Center in Manhattan, NY. Additional data from US minority groups and Brazil were used for external comparison. Substantial variation in ancestral origin was observed for both African Americans and Hispanics; data from the latter group overlapped with both Mexican Americans and Brazilians in the external data sets. A pooled analysis of the African Americans and Hispanics from NY demonstrated a broad continuum of ancestral origin making classification by race/ethnicity uninformative. Selected loci harboring variants associated with medical traits and drug response confirmed substantial within-and between-group heterogeneity. Conclusion: As a consequence of these complementary levels of heterogeneity group labels offered no guidance at the individual level. These findings demonstrate the complexity involved in clinical translation of the results from genome-wide association studies and suggest that in the genomic era conventional racial/ethnic labels are of little value.National Heart Lung and Blood Institute (NHLBI/NIH)[RO1 HL53353]Andrea and Charles Bronfman Philantropie