Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Clinical and neuroimaging correlates of progression of mild parkinsonian signs in community-dwelling older adults

IntroductionMild parkinsonian signs (MPS) are associated with morbidity. Identification of MPS progression markers may be vital for preventive management, yet has not been pursued. This study aimed to ascertain clinical/neuroimaging features predictive of MPS progression.Methods205 participants in the Health ABC Study were included. MPS was defined using published guidelines. MPS progression was evaluated by determining UPDRS-III change between baseline and follow-up ≥2 years later. Standard brain MRI and DTI were obtained at baseline. Correlation coefficients between demographics, vascular risk factors, imaging markers, and UPDRS-III change were adjusted for follow-up time. Linear regression was used to adjust for possible confounders in the relationship between imaging markers and MPS progression.Results30% of participants had baseline MPS. Demographics and risk factors did not differ significantly between participants with MPS (MPS+) and without MPS (MPS-). Mean follow-up time was 3.8±0.8 years. Older age, male gender, diabetes were associated with faster rate of UPDRS-III change in MPS- but not MPS+&nbsp;participants. Among MPS- participants, the only imaging marker associated with faster UPDRS-III progression was higher gray matter mean diffusivity (MD), widespread in various cortico-subcortical bihemispheric regions, independent of age, gender, diabetes. No imaging features were associated with UPDRS-III change among MPS+&nbsp;participants.ConclusionsLower gray matter integrity predicted MPS progression in those who did not have baseline MPS. Microstructural imaging may capture early changes related to MPS development, prior to macrostructural change. Any future management promoting gray matter preservation may inhibit MPS development

Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits

NAFLD is a spectrum of disease that ranges from steatosis to steatohepatitis (nonalcoholic steatohepatitis or NASH: inflammation around the fat) to fibrosis/cirrhosis. Hepatic steatosis can be measured non-invasively using computed tomography (CT) whereas NASH/fibrosis is assessed histologically. The genetic underpinnings of NAFLD remain to be determined. Here we estimate that 26%–27% of the variation in CT measured hepatic steatosis is heritable or genetic. We identify three variants near PNPLAL3, NCAN, and PPP1R3B that associate with CT hepatic steatosis and show that variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B, associate with histologic lobular inflammation/fibrosis. Variants in or near NCAN, GCKR, and PPP1R3B associate with altered serum lipid levels, whereas those in or near LYPLAL1 and PNPLA3 do not. Variants near GCKR and PPP1R3B also affect glycemic traits. Thus, we show that NAFLD is genetically influenced and expand the number of common genetic variants that associate with this trait. Our findings suggest that development of hepatic steatosis, NASH/fibrosis, or abnormalities in metabolic traits are probably influenced by different metabolic pathways that may represent distinct therapeutic targets

COVID-19 vaccine booster dose needed to achieve Omicron-specific neutralisation in nursing home residents

BACKGROUND: Nursing home (NH) residents have borne a disproportionate share of SARS-CoV-2 morbidity and mortality. Vaccines have limited hospitalisation and death from earlier variants in this vulnerable population. With the rise of Omicron and future variants, it is vital to sustain and broaden vaccine-induced protection. We examined the effect of boosting with BNT162b2 mRNA vaccine on humoral immunity and Omicron-specific neutralising activity among NH residents and healthcare workers (HCWs). METHODS: We longitudinally enrolled 85 NH residents (median age 77) and 48 HCWs (median age 51), and sampled them after the initial vaccination series; and just before and 2 weeks after booster vaccination. Anti-spike, anti-receptor binding domain (RBD) and neutralisation titres to the original Wuhan strain and neutralisation to the Omicron strain were obtained. FINDINGS: Booster vaccination significantly increased vaccine-specific anti-spike, anti-RBD, and neutralisation levels above the pre-booster levels in NH residents and HCWs, both in those with and without prior SARS-CoV-2 infection. Omicron-specific neutralisation activity was low after the initial 2 dose series with only 28% of NH residents’ and 28% HCWs’ titres above the assay's lower limit of detection. Omicron neutralising activity following the booster lifted 86% of NH residents and 93% of HCWs to the detectable range. INTERPRETATION: With boosting, the vast majority of HCWs and NH residents developed detectable Omicron-specific neutralising activity. These data provide immunologic evidence that strongly supports booster vaccination to broaden neutralising activity and counter waning immunity in the hope it will better protect this vulnerable, high-risk population against the Omicron variant

Agents of change: establishing quality improvement collaboratives to improve adherence to Australian clinical guidelines for dementia care

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background Dissemination of clinical practice guidelines alone is insufficient to create meaningful change in clinical practice. Quality improvement collaborative models have potential to address the evidence-practice gap in dementia care because they capitalise on known knowledge translation enablers and incorporate optimal approaches to implementation. Non-pharmacological interventions focused on promoting independence are effective and favoured by people with dementia and their carers but are not routinely implemented. The objective of this translational project is to assess the impact of quality improvement collaboratives (QICs) on adherence to non-pharmacological recommendations from the Clinical Practice Guidelines for Dementia in Australia. Methods This project will employ an interrupted time-series design with process evaluation to assess the impact, uptake, feasibility, accessibility, cost, and sustainability of the QICs over 18 months. Thirty clinicians from across Australia will be invited to join the QICs to build their capacity in leading innovation in dementia care. Clinicians will participate in a training program and be supported to develop and implement a quality improvement project unique to their service context using plan-do-study-act cycles. Regular online meetings with their peers in the QIC will facilitate benchmarking and problem-solving. Clinicians will describe their practice via monthly checklists, and guideline adherence will be determined against a set of defined criteria. Phone interviews with up to 180 client dyads will be used to assess satisfaction with care and client outcomes. Clinician interviews and field note data will be used to explore implementation and costs. Involvement of people with dementia and carers will be embedded in the study design, conduct, and reporting, in addition to clinical and industry expertise. Discussion The quality of dementia care in Australia is largely dependent on the clinician involved and the extent to which they apply best available evidence in their practice. This study will determine the elements of this multifaceted implementation strategy that contributed to guideline adherence and client outcomes. The findings will inform future translational approaches to improving care and outcomes for people with dementia and their carers.Funding for this study is provided by the NHRMC Partnership Centre for Dealing with Cognitive and Related Functional Decline in Older People (grant no. CDPC1327) and by the NHRMC National Institute for Dementia Research (grant no. 1135667). Both funding bodies peer reviewed the project but neither had any role in its design or data collection, analysis, or interpretation. Ian Cameron is supported by an Australian Health and Medical Research Council Senior Practitioner Fellowship. Kate Laver is supported by an Australian Health and Medical Research Council Dementia Research Development Fellowship

Mental Ill Health, Recovery and the Family Assemblage

The recovery approach is now among the most influential paradigms shaping mental health policy and practice across the English-speaking world. While recovery is normally presented as a deeply personal process, critics have challenged the individualism underpinning this view. A growing literature on “family recovery” explores the ways in which people, especially parents with mental ill health, can find it impossible to separate their own recovery experiences from the processes of family life. While sympathetic to this literature, we argue that it remains limited by its anthropocentricity, and therefore struggles to account for the varied human and nonhuman entities and forces involved in the creation and maintenance of family life. The current analysis is based on an ethnographic study conducted in Australia, which focused on families in which the father experiences mental ill health. We employ the emerging concept of the “family assemblage” to explore how the material, social, discursive and affective components of family life enabled and impeded these fathers’ recovery trajectories. Viewing families as heterogeneous assemblages allows for novel insights into some of the most basic aspects of recovery, challenging existing conceptions of the roles and significance of emotion, identity and agency in the family recovery process