A regression based transmission/disequilibrium test for binary traits: the power of joint tests for linkage and association

BACKGROUND: In this analysis we applied a regression based transmission disequilibrium test to the binary trait presence or absence of Kofendred Personality Disorder in the Genetic Analysis Workshop 14 (GAW14) simulated dataset and determined the power and type I error rate of the method at varying map densities and sample sizes. To conduct this transmission disequilibrium test, the logit transformation was applied to a binary outcome and regressed on an indicator variable for the transmitted allele from informative matings. All 100 replicates from chromosomes 1, 3, 5, and 9 for the Aipotu and the combined Aipotu, Karangar, and Danacaa populations were used at densities of 3, 1, and 0.3 cM. Power and type I error were determined by the number of replicates significant at the 0.05 level. RESULTS: The maximum power to detect linkage and association with the Aipotu population was 93% for chromosome 3 using a 0.3-cM map. For chromosomes 1, 5, and 9 the power was less than 10% at the 3-cM scan and less than 22% for the 0.3-cM map. With the larger sample size, power increased to 38% for chromosome 1, 100% for chromosome 3, 31% for chromosome 5, and 23% for chromosome 9. Type I error was approximately 7%. CONCLUSION: The power of this method is highly dependent on the amount of information in a region. This study suggests that single-point methods are not particularly effective in narrowing a fine-mapping region, particularly when using single-nucleotide polymorphism data and when linkage disequilibrium in the region is variable

β2-Adrenergic receptor promoter haplotype influences the severity of acute viral respiratory tract infection during infancy: a prospective cohort study.

BACKGROUND: Despite the significant interest in β2-Adrenergic receptor (ADRB2) polymorphisms related to asthma, whether ADRB2 genetic variants are similarly associated with acute respiratory tract infections have not been studied. We hypothesized that genetic variants in ADRB2 associated with a response to asthma therapy during an asthma exacerbation were also associated with severity of acute respiratory tract infections. METHODS: To test this hypothesis, we genotyped 5 common polymorphisms in the promoter region and coding block of the ADRB2 gene (loci -2387, -2274, -1343, +46, and +79) from 374 Caucasian and African American term infants who were enrolled at the time of acute respiratory illness over four respiratory viral seasons. Severity of respiratory tract infections was measured using a bronchiolitis severity score (BSS; range = 0-12, clinically significant difference = 0.5) with a higher score indicating more severe disease. We assigned the promoter, coding and combined promoter and coding haplotypes to the unphased genotype data. The associations between each of these five single-nucleotide polymorphisms (SNPs) as well as the haplotypes and infant BSS were analyzed using nonparametric univariate analysis and multivariable proportional odds model separately in Caucasians and African Americans. RESULTS: There was no significant association between infant BSS and each of the SNPs in both Caucasians and African Americans. However, promoter haplotype CCA was associated with a decreased BSS in African Americans in a dose dependent manner. The median (interquartile range) BSS of infants with no copies of the CCA haplotype, one copy, and two copies of the CCA haplotype were 5.5 (2.0, 8.0), 4.0 (1.0, 7.5), and 3.0 (1.0, 4.0), respectively. This dose dependent relationship persisted after adjusting for infant age, gender, daycare exposure, secondhand smoke exposure, prior history of breastfeeding, siblings at home, and enrollment season (adjusted odds ratio: 0.59, 95 % confidence interval: 0.36, 0.98). There was no similar protective relationship of haplotype CCA on severity of respiratory tract infections identified in Caucasians. CONCLUSIONS: ADRB2 genotype may be predictive of severity of acute respiratory tract infections in African Americans, and potentially identify a subset of infants who may respond to beta-agonist therapy

Multivariate association analysis of the components of metabolic syndrome from the Framingham Heart Study

Metabolic syndrome, by definition, is the manifestation of multiple, correlated metabolic impairments. It is known to have both strong environmental and genetic contributions. However, isolating genetic variants predisposing to such a complex trait has limitations. Using pedigree data, when available, may well lead to increased ability to detect variants associated with such complex traits. The ability to incorporate multiple correlated traits into a joint analysis may also allow increased detection of associated genes. Therefore, to demonstrate the utility of both univariate and multivariate family-based association analysis and to identify possible genetic variants associated with metabolic syndrome, we performed a scan of the Affymetrix 50 k Human Gene Panel data using 1) each of the traits comprising metabolic syndrome: triglycerides, high-density lipoprotein, systolic blood pressure, diastolic blood pressure, blood glucose, and body mass index, and 2) a composite trait including all of the above, jointly. Two single-nucleotide polymorphisms within the cholesterol ester transfer protein (CETP) gene remained significant even after correcting for multiple testing in both the univariate (p < 5 × 10-7) and multivariate (p < 5 × 10-9) association analysis. Three genes met significance for multiple traits after correction for multiple testing in the univariate analysis, while five genes remained significant in the multivariate association. We conclude that while both univariate and multivariate family-based association analysis can identify genes of interest, our multivariate approach is less affected by multiple testing correction and yields more significant results

“Take more laxatives was their answer to everything.”:A qualitative exploration of the patient, carer and healthcare professional experience of constipation in specialist palliative care

Constipation is a major problem for many older adults, more so for those who are receiving specialist palliative care. However, limited research reports the subjective experiences of constipation, despite evidenced differences between the healthcare professional and patient/carer perspective. The main aim of this study is to explore the experience of how constipation is assessed and managed within specialist palliative care from the patient, carer and healthcare professional perspective. Exploratory, qualitative design, utilising focus groups and interviews, and analysed using thematic analysis. Six focus groups with 27 healthcare professionals and semi-structured interviews with 13 patients and 5 family caregivers in specialist palliative care units across three regions of the United Kingdom. Constipation impacted physically, psychologically and socially on patients and families; however, they felt staff relegated it on the list of importance. Lifestyle modifications implemented at home were not incorporated into their specialist palliative care plan within the hospice. Comparatively, healthcare professionals saw constipation solely as a physical symptom. Assessment focused on the physical elements of constipation, and management was pharmacologically driven. Healthcare professionals reported patient embarrassment as a barrier to communicating about bowel care, whereas patients wanted staff to initiate communication and discuss constipation openly. Assessment and management of constipation may not yet reflect the holistic palliative care model. A focus on the pharmacological management may result in lifestyle modifications being underutilised. Healthcare professionals also need to be open to initiate communication on bowel care and consider non-pharmacological approaches. It is important that patients and families are supported in self-care management, alongside standardised guidelines for practice and for healthcare professionals to facilitate this

Association of Genetic Loci with Sleep Apnea in European Americans and African-Americans: The Candidate Gene Association Resource (CARe)

Although obstructive sleep apnea (OSA) is known to have a strong familial basis, no genetic polymorphisms influencing apnea risk have been identified in cross-cohort analyses. We utilized the National Heart, Lung, and Blood Institute (NHLBI) Candidate Gene Association Resource (CARe) to identify sleep apnea susceptibility loci. Using a panel of 46,449 polymorphisms from roughly 2,100 candidate genes on a customized Illumina iSelect chip, we tested for association with the apnea hypopnea index (AHI) as well as moderate to severe OSA (AHI≥15) in 3,551 participants of the Cleveland Family Study and two cohorts participating in the Sleep Heart Health Study. Among 647 African-Americans, rs11126184 in the pleckstrin (PLEK) gene was associated with OSA while rs7030789 in the lysophosphatidic acid receptor 1 (LPAR1) gene was associated with AHI using a chip-wide significance threshold of p-value<2×$10^{−6}$. Among 2,904 individuals of European ancestry, rs1409986 in the prostaglandin E2 receptor (PTGER3) gene was significantly associated with OSA. Consistency of effects between rs7030789 and rs1409986 in LPAR1 and PTGER3 and apnea phenotypes were observed in independent clinic-based cohorts. Novel genetic loci for apnea phenotypes were identified through the use of customized gene chips and meta-analyses of cohort data with replication in clinic-based samples. The identified SNPs all lie in genes associated with inflammation suggesting inflammation may play a role in OSA pathogenesis