Calf pre-weaning traits and immunoglobulin response to bovine viral diarrhea virus vaccination

Calfhood vaccination for bovine viral diarrhea virus (BVDV) is a relatively new concept, and protocols are evolving. Our objective was to determine effects of BVDV type I vaccination protocol, calf behavior (chute score, and chute exit velocity), and gender on calf gain and immunoglobulin (Ig) response. Crossbred calves (n = 64) were randomly allotted to one of two vaccination protocols. In protocol 1, calves were vaccinated at 60 d of age (d 0) and at weaning (d 147). Calves assigned to protocol 2 were vaccinated against BVDV type I at 21 d prior to (d 126) and at weaning (d 147). Blood samples were collected from half of the calves in each protocol group on d 0 (60 days of age), d 21, d 126 (21 days prior to weaning), and d 147 (at weaning); serum was harvested and Ig titers were determined. Titers for BVDV type I were transformed (log base 2) and analyzed using a mixed model procedure. Calves vaccinated at d 0 and weaning had larger (P \u3c 0.0001) titers than calves vaccinated at d 126 and weaning (7.5 ± 0.36 and 5.1 ± 0.36, respectively). Mean BVDV titers were larger (P \u3c 0.0001) on d 147 when compared with d 126, d 21, and d 0 (8.3 ± 0.39, 5.1 ± 0.40, 5.9 ± 0.39 and 5.7 ± 0.39, respectively). A treatment × day interaction (P \u3c 0.0001) also affected BVDV titers. However, BVDV titers were not affected (P \u3e 0.05) by calf gender, chute score, or chute exit velocity. Weaning weight and pre-weaning average daily gain (ADG) were not related to BVDV type I titers. This study indicated that vaccinating beef calves against BVDV was effective in triggering an Ig response. Furthermore, our results suggest that calves should be vaccinated against BVDV type I at 60 d of age for greater disease resistance

Cardiopulmonary Function and Age-Related Decline Across the Breast Cancer Survivorship Continuum

To evaluate cardiopulmonary function (as measured by peak oxygen consumption [VO2peak]) across the breast cancer continuum and its prognostic significance in women with metastatic disease

Loss-of-Function Genomic Variants Highlight Potential Therapeutic Targets for Cardiovascular Disease

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10−8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD

Global Biobank Meta-analysis Initiative:Powering genetic discovery across human disease

Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)—a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.</p

GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer

Correction: Volume12, Issue1 Article Number7354 DOI10.1038/s41467-021-27675-w PublishedDEC 16 2021Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors. Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. Here, the authors conduct a GWAS and suggest protective effect of higher TSH on risk of thyroid cancer and goitre.Peer reviewe

Author Correction:GWAS of thyroid stimulating hormone highlights the pleiotropic effects and inverse association with thyroid cancer

The original version of this article contained an error in the results, in the second paragraph of the subsection entitled “Fine-mapping for potentially causal variants among TSH loci”, in which effect sizes for two variants were incorrectly reported

Genome-wide analysis yields new loci associating with aortic valve stenosis

Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 × 10−22) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 × 10−13). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 × 10−10) and aortic root diameter (P = 1.30 × 10−8), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 × 10−3) and coronary artery disease (OR = 1.05, P = 9.3 × 10−5). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors

A survey of aortic disease biorepository participants’ preferences for return of research genetic results

There is ongoing debate on whether and what research genetic results to return to study participants. To date, no study in this area has focused on aortopathy populations despite known genes that are clinically actionable. Participants (n = 225, 79% male, mean age = 61 years) with an aortopathy were surveyed to assess preferences for receiving research genetic results. Participants were - very- or - extremely likely- to want results for pathogenic variants in aortopathy genes with implications for family members (81%) or that would change medical management (76%). Similarly, participants were - very- or - extremely likely- to want actionable secondary findings related to cancer (75%) or other cardiac diseases (70%). Significantly lower interest was observed for non- actionable findings- pathogenic variants in aortopathy genes that would not change medical management (51%) and variants of uncertain significance (38%) (p 63%) were accepting of any means of return; however, a substantial minority (18%- 38%) deemed certain technological means unacceptable (e.g., patient portal). Over 90% of participants reported that a range of health professionals, including cardiovascular specialists, genetics specialists, and primary care providers, were acceptable to return results. Participants with aortopathies are highly interested in research genetic results perceived to be medically actionable for themselves or family members. Participants are accepting of a variety of means for returning results. Findings suggest that research participants should be asked what results are preferred at time of informed consent and that genetic counseling may clarify implications of results that are not personally medically actionable.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/168345/1/jgc41341_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/168345/2/jgc41341-sup-0004-Supinfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/168345/3/jgc41341.pd