Homozygosity by descent mapping of blood pressure in the Old Order Amish: evidence for sex specific genetic architecture

<p>Abstract</p> <p>Background</p> <p>High blood pressure is a well established risk factor for morbidity and mortality acting through heart disease, stroke and cardiovascular disease. Genome wide scans have linked regions of nearly every human chromosome to blood pressure related traits. We have capitalized on beneficial qualities of the Old Order Amish of Lancaster, PA, a closed founder population with a relatively small number of founders, to perform a genome wide homozygosity by descent mapping scan. Each individual in the study has a non zero probability of consanguinity. Systolic and diastolic blood pressures are shown to have appreciable dominance variance components.</p> <p>Results</p> <p>Areas of two chromosomes were identified as suggestive of linkage to SBP and 5 areas to DBP in either the overall or sex specific analyses. The strongest evidence for linkage in the overall sample was to Chromosome 18q12 (LOD = 2.6 DBP). Sex specific analyses identified a linkage on Chromosome 4p12-14 (LOD in men only = 3.4 SBP). At Chromosome 2q32-33, an area where we previously reported significant evidence for linkage to DBP using a conventional identity by descent approach, the LOD was 1.4; however an appreciable sex effect was observed with men accounting for most of the linkage (LOD in men only = 2.6).</p> <p>Conclusion</p> <p>These results add evidence to a sex specific genetic architecture to blood pressure related traits, particularly in regions of linkage on chromosome 2, 4 and 18.</p

Combinatorial Mismatch Scan (CMS) for loci associated with dementia in the Amish

BACKGROUND: Population heterogeneity may be a significant confounding factor hampering detection and verification of late onset Alzheimer's disease (LOAD) susceptibility genes. The Amish communities located in Indiana and Ohio are relatively isolated populations that may have increased power to detect disease susceptibility genes. METHODS: We recently performed a genome scan of dementia in this population that detected several potential loci. However, analyses of these data are complicated by the highly consanguineous nature of these Amish pedigrees. Therefore we applied the Combinatorial Mismatch Scanning (CMS) method that compares identity by state (IBS) (under the presumption of identity by descent (IBD)) sharing in distantly related individuals from such populations where standard linkage and association analyses are difficult to implement. CMS compares allele sharing between individuals in affected and unaffected groups from founder populations. Comparisons between cases and controls were done using two Fisher's exact tests, one testing for excess in IBS allele frequency and the other testing for excess in IBS genotype frequency for 407 microsatellite markers. RESULTS: In all, 13 dementia cases and 14 normal controls were identified who were not related at least through the grandparental generation. The examination of allele frequencies identified 24 markers (6%) nominally (p ≤ 0.05) associated with dementia; the most interesting (empiric p ≤ 0.005) markers were D3S1262, D5S211, and D19S1165. The examination of genotype frequencies identified 21 markers (5%) nominally (p ≤ 0.05) associated with dementia; the most significant markers were both located on chromosome 5 (D5S1480 and D5S211). Notably, one of these markers (D5S211) demonstrated differences (empiric p ≤ 0.005) under both tests. CONCLUSION: Our results provide the initial groundwork for identifying genes involved in late-onset Alzheimer's disease within the Amish community. Genes identified within this isolated population will likely play a role in a subset of late-onset AD cases across more general populations. Regions highlighted by markers demonstrating suggestive allelic and/or genotypic differences will be the focus of more detailed examination to characterize their involvement in dementia

The Catalina Surveys Periodic Variable Star Catalog

We present ~47,000 periodic variables found during the analysis of 5.4 million variable star candidates within a 20,000 square degree region covered by the Catalina Surveys Data Release-1 (CSDR1). Combining these variables with type-ab RR Lyrae from our previous work, we produce an on-line catalog containing periods, amplitudes, and classifications for ~61,000 periodic variables. By cross-matching these variables with those from prior surveys, we find that > 90% of the ~8,000 known periodic variables in the survey region are recovered. For these sources we find excellent agreement between our catalog and prior values of luminosity, period and amplitude, as well as classification. We investigate the rate of confusion between objects classified as contact binaries and type-c RR Lyrae (RRc's) based on periods, colours, amplitudes, metalicities, radial velocities and surface gravities. We find that no more than few percent of these variables in these classes are misidentified. By deriving distances for this clean sample of ~5,500 RRc's, we trace the path of the Sagittarius tidal streams within the Galactic halo. Selecting 146 outer-halo RRc's with SDSS radial velocities, we confirm the presence of a coherent halo structure that is inconsistent with current N-body simulations of the Sagittarius tidal stream. We also find numerous long-period variables that are very likely associated within the Sagittarius tidal streams system. Based on the examination of 31,000 contact binary light curves we find evidence for two subgroups exhibiting irregular lightcurves. One subgroup presents significant variations in mean brightness that are likely due to chromospheric activity. The other subgroup shows stable modulations over more than a thousand days and thereby provides evidence that the O'Connell effect is not due to stellar spots.Comment: Accepted ApJS, 43 pages, 9 tables, 44 figures (some at reduced resolution

Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci

To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p <2.4 x 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 x 10(-8)). Finally, a composite genetic score of SNPs from new and established T2D signals was significantly associated with increased risk of diabetes in African-American, Hispanic, and Asian populations. In summary, large-scale meta-analysis involving a dense gene-centric approach has uncovered additional loci and variants that contribute to T2D risk and suggests substantial overlap of T2D association signals across multiple ethnic groups

Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding

Baseline cardiometabolic profiles and SARS-CoV-2 infection in the UK Biobank.

BackgroundSARS-CoV-2 is a rapidly spreading coronavirus responsible for the Covid-19 pandemic, which is characterized by severe respiratory infection. Many factors have been identified as risk factors for SARS-CoV-2, with much early attention being paid to body mass index (BMI), which is a well-known cardiometabolic risk factor.ObjectiveThis study seeks to examine the impact of additional baseline cardiometabolic risk factors including high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), Apolipoprotein A-I (ApoA-I), Apolipoprotein B (ApoB), triglycerides, hemoglobin A1c (HbA1c) and diabetes on the odds of testing positive for SARS-CoV-2 in UK Biobank (UKB) study participants.MethodsWe examined the effect of BMI, lipid profiles, diabetes and alcohol intake on the odds of testing positive for SARS-Cov-2 among 9,005 UKB participants tested for SARS-CoV-2 from March 16 through July 14, 2020. Odds ratios and 95% confidence intervals were computed using logistic regression adjusted for age, sex and ancestry.ResultsHigher BMI, Type II diabetes and HbA1c were associated with increased SARS-CoV-2 odds (p ConclusionElevated HDL-C and ApoA-I levels were associated with reduced odds of testing positive for SARS-CoV-2, while higher BMI, type II diabetes and HbA1c were associated with increased odds. The effects of BMI, type II diabetes and HbA1c levels were no longer significant after controlling for HDL-C, suggesting that these effects may be mediated in part through regulation of HDL-C levels. In summary, our study suggests that baseline HDL-C level may be useful for stratifying SARS-CoV-2 infection risk and corroborates the emerging picture that HDL-C may confer protection against sepsis in general and SARS-CoV-2 in particular

Paragon (ANZGOG-0903) phase 2 study of anastrozole in women with estrogen or progesterone receptor-positive platinum-resistant or -refractory recurrent ovarian cancer

Background: There is some evidence that a subset of patients with recurrent ovarian cancer may benefit from antiestrogen therapy. The Paragon study is a basket protocol that includes a series of phase 2 trials investigating the activity of anastrozole in patients with estrogen or progesterone receptorYpositive recurrent gynecological cancers. We report the results of treatment in patients with platinum-resistant or -refractory recurrent epithelial ovarian cancer. Methods: Postmenopausal women who had estrogen and/or progesterone receptorYpositive platinum-resistant or platinum-refractory recurrent ovarian cancer and disease measurable by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 or GCIG (Gynecologic Cancer InterGroup) CA-125 criteria were eligible. Patients received anastrozole 1 mg daily until progression or unacceptable toxicity. The study was prospectively registered (ACTRN12610000796088). Results: There were 49 evaluable patients, and clinical benefit was observed in 13 (27%; 95%confidence interval [CI], 16%Y40%). Therewere no complete or partial RECIST version 1.1 responses.Clinical benefitwas associatedwith higher global quality-of-life scores.Median progression-free survival was 2.7 months (95% CI, 2.0Y2.8 months). The median duration of clinical benefit was 2.8 months (95% CI, 2.6Y5.7 months). Most patients (83%) progressed within 6months. Seven patients continued on treatment for longer than 6months. Anastrozole was well tolerated in most patients. Subgroup analysis suggested greater clinical benefit in patients with tumors with estrogen-receptor histoscore ofmore than 200, but this differencewas not statistically significant. Conclusions: A subset of patientswith estrogen- or progesterone-positive platinum-resistant or platinum-refractory recurrent epithelial ovarian cancers derives clinical benefit from anastrozole, with acceptable toxicity. The challenge remains how to identify them