Dissecting the Reduced Penetrance of Putative Loss-of-Function Variants in Population-Scale Biobanks.

Loss-of-function variants (LoFs) disrupt the activity of their impacted gene. They are often associated with clinical phenotypes, including autosomal dominant diseases driven by haploinsufficiency. Recent analyses using biobanks have suggested that LoF penetrance for some haploinsufficient disorders may be low, an observation that has important implications for population genomic screening.

Identification of the Molecular Components of Enhancer-Mediated Gene Expression Variation in Multiple Tissues Regulating Blood Pressure.

Background: Inter-individual variation in blood pressure (BP) arises in part from sequence variants within enhancers modulating the expression of causal genes. We propose that these genes, active in tissues relevant to BP physiology, can be identified from tissue-level epigenomic data and genotypes of BP-phenotyped individuals.

Methods: We used chromatin accessibility data from the heart, adrenal, kidney, and artery to identify cis-regulatory elements (CREs) in these tissues and estimate the impact of common human single-nucleotide variants within these CREs on gene expression, using machine learning methods.

Genetic ancestry and diagnostic yield of exome sequencing in a diverse population.

It has been suggested that diagnostic yield (DY) from Exome Sequencing (ES) may be lower among patients with non-European ancestries than those with European ancestry. We examined the association of DY with estimated continental/subcontinental genetic ancestry in a racially/ethnically diverse pediatric and prenatal clinical cohort. Cases (N = 845) with suspected genetic disorders underwent ES for diagnosis.

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation.

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel).

Diagnostic Yield of Exome Sequencing in a Diverse Pediatric and Prenatal Population is not Associated with Genetic Ancestry.

Purpose: It has been hypothesized that diagnostic yield (DY) from Exome Sequencing (ES) may be lower among patients with non-European ancestries than those with European ancestry. We examined the association of DY with estimated continental genetic ancestry in a racially/ethnically diverse pediatric and prenatal clinical cohort.

Methods: Cases (N=845) with suspected genetic disorders underwent ES for diagnosis.

Global priorities for large-scale biomarker-based prospective cohorts.

The focus of this paper is on strategic approaches for establishing population-based prospective cohorts that collect and store biological samples from very large numbers of participants to help identify the determinants of common health outcomes. In particular, it aims to address key issues related to investigation of genetic, as well as social, environmental, and ancestral, diversity; generation of detailed genetic and other types of assay data; collection of detailed lifestyle and environmental exposure information; follow-up and characterization of incident health outcomes; and overcoming obstacles to data sharing and access (including capacity building). It concludes that there is a need for strategic planning at an international level (rather than the current approach) toward the development of a carefully selected set of deeply characterized large-scale prospective cohorts that are readily accessible by researchers around the world.

A large genome-wide association study of QT interval length utilizing electronic health records.

QT interval length is an important risk factor for adverse cardiovascular outcomes; however, the genetic architecture of QT interval remains incompletely understood. We conducted a genome-wide association study of 76,995 ancestrally diverse Kaiser Permanente Northern California members enrolled in the Genetic Epidemiology Research on Adult Health and Aging cohort using 448,517 longitudinal QT interval measurements, uncovering 9 novel variants, most replicating in 40,537 individuals in the UK Biobank and Population Architecture using Genomics and Epidemiology studies. A meta-analysis of all 3 cohorts (n = 117,532) uncovered an additional 19 novel variants.

Effect of mirror therapy in the treatment of phantom limb pain in amputees: A systematic review of randomized placebo-controlled trials does not find any evidence of efficacy.

Background And Objective: Phantom limb pain (PLP) concerns >50% of amputees and has a negative impact on their rehabilitation, mental health and quality of life. Mirror therapy (MT) is a promising strategy, but its effectiveness remains controversial. We performed a systematic review to: (i) evaluate the effectiveness of MT versus placebo in reducing PLP, and (ii) determine MT effect on disability and quality of life.

Polygenic Risk Score and Statin Relative Risk Reduction for Primary Prevention of Myocardial Infarction in a Real-World Population.

Genetic substudies of randomized controlled trials demonstrate that high coronary heart disease (CHD) polygenic risk score modifies statin CHD relative risk reduction; it is unknown if the association extends to statin users undergoing routine care. We sought to determine how statin effectiveness is modified by CHD polygenic risk score in a real-world cohort of participants without previous myocardial infarction. We determined CHD polygenic risk scores in participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort.

Modest effect of statins on fasting glucose in a longitudinal electronic health record based cohort.

Background: Prior studies of the glycemic effect of statins have been inconsistent. Also, most studies have only considered a short duration of statin use; the effect of long-term statin use on fasting glucose (FG) has not been well examined. The aim of this work is to investigate the effect of long-term statin exposure on FG levels.

Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia.

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8.

Self-Reported Pain and Emotional Reactivity in Bipolar Disorder: A Prospective FACE-BD Study.

In patients with bipolar disorder (BD), pain prevalence is close to 30%. It is important to determine whether pain influences BD course and to identify factors associated with pain in BD in order to guide BD management. This naturalistic, prospective study used data on 880 patients with BD from the French FACE-BD cohort who were divided into two groups according to the presence or absence of pain.

Neutrophil-to-lymphocyte ratio (NLR) variations in relationship with childhood maltreatment in patients with anorexia nervosa: a retrospective cohort study.

Purpose: Anorexia nervosa (AN) is a serious mental illness. It is frequently accompanied by a history of childhood maltreatment (CM) that may constitute a specific ecophenotype in patients with eating disorders necessitating special assessment and management. This retrospective study tested whether in patients with AN, CM-related chronic stress may manifest through low-grade inflammation reflected by an increase in white blood cell ratios (neutrophil-to-lymphocyte ratio, NLR, platelet-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio).

The difficulties of broad data sharing in genomic medicine: Empirical evidence from diverse participants in prenatal and pediatric clinical genomics research.

Purpose: This study aimed to understand broad data sharing decisions among predominantly underserved families participating in genomic research.

Methods: Drawing on clinic observations, semistructured interviews, and survey data from prenatal and pediatric families enrolled in a genomic medicine study focused on historically underserved and underrepresented populations, this paper expands empirical evidence regarding genomic data sharing communication and decision-making.

Results: One-third of parents declined to share family data, and pediatric participants were significantly more likely to decline than prenatal participants.