Preimplantation genetic testing for polygenic disorders: Viewpoints of reproductive genetic counselors and reproductive endocrinology and infertility specialists in the United States.

The purpose of this study was to assess awareness of preimplantation genetic testing (PGT) for polygenic disorders (PGT-P) and viewpoints surrounding PGT among reproductive genetic counselors (GCs) and reproductive endocrinology infertility physicians (REIs) in the United States. GCs and REIs were recruited via professional groups to complete an anonymous online survey that assessed awareness of PGT-P, motivating factors that are considered in recommending PGT-P and views on clinical use of PGT. In our sample of 82 GCs and 54 REIs, 80% reported having heard of PGT-P, 52% answered yes or maybe to whether patients should have the option of PGT-P for polygenic conditions, and only 18% answered yes or maybe to whether they would recommend it to their patients.

Gut microbe-derived metabolites and the risk of cardiovascular disease in the METSIM cohort.

Background: An association between gut microbes and cardiovascular disease (CVD) has been established, but the underlying mechanisms remain largely unknown.

Methods: We conducted a secondary analysis of the cross-sectional data obtained from the Metabolic Syndrome in Men (METSIM) population-based cohort of 10,194 Finnish men (age = 57.65 ± 7.

Cultural, demographic, and other non-demographic factors associated with cancer genetic counseling patients' appointment accompaniment preferences in the United States.

Although the presence of companion(s) in a genetic counseling session can positively influence session dynamics, research has found that some patients prefer to attend their appointments alone. To date, no studies have examined patient accompaniment preferences across different cultural groups in the context of genetic counseling. This quantitative study aimed to identify factors associated with individual preferences in accompaniment at cancer genetic counseling appointments in a sample (N = 130) of Hispanic/Latine (n = 29) and non-Hispanic/Latine White (n = 101) participants at a large academic medical institution.

Relationships and Mendelian Randomization of Gut Microbe-Derived Metabolites with Metabolic Syndrome Traits in the METSIM Cohort.

The role of gut microbe-derived metabolites in the development of metabolic syndrome (MetS) remains unclear. This study aimed to evaluate the associations of gut microbe-derived metabolites and MetS traits in the cross-sectional Metabolic Syndrome In Men (METSIM) study. The sample included 10,194 randomly related men (age 57.

Genome-wide mapping of brain phenotypes in extended pedigrees with strong genetic loading for bipolar disorder.

Bipolar disorder is a highly heritable illness, associated with alterations of brain structure. As such, identification of genes influencing inter-individual differences in brain morphology may help elucidate the underlying pathophysiology of bipolar disorder (BP). To identify quantitative trait loci (QTL) that contribute to phenotypic variance of brain structure, structural neuroimages were acquired from family members (n = 527) of extended pedigrees heavily loaded for bipolar disorder ascertained from genetically isolated populations in Latin America.

Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates.

Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP.

Genetic analysis of activity, brain and behavioral associations in extended families with heavy genetic loading for bipolar disorder.

Background: Disturbed sleep and activity are prominent features of bipolar disorder type I (BP-I). However, the relationship of sleep and activity characteristics to brain structure and behavior in euthymic BP-I patients and their non-BP-I relatives is unknown. Additionally, underlying genetic relationships between these traits have not been investigated.

Whole blood transcriptome analysis in bipolar disorder reveals strong lithium effect.

Background: Bipolar disorder (BD) is a highly heritable mood disorder with complex genetic architecture and poorly understood etiology. Previous transcriptomic BD studies have had inconsistent findings due to issues such as small sample sizes and difficulty in adequately accounting for confounders like medication use.

Methods: We performed a differential expression analysis in a well-characterized BD case-control sample (Nsubjects = 480) by RNA sequencing of whole blood.

Genetic Deficiency of Flavin-Containing Monooxygenase 3 ( Fmo3) Protects Against Thrombosis but Has Only a Minor Effect on Plasma Lipid Levels-Brief Report.

Objective- FMO (flavin-containing monooxygenase) 3 converts bacterial-derived trimethylamine to trimethylamine N-oxide (TMAO), an independent risk factor for cardiovascular disease. We generated FMO3 knockout (FMO3KO) mouse to study its effects on plasma TMAO, lipids, glucose/insulin metabolism, thrombosis, and atherosclerosis. Approach and Results- Previous studies with an antisense oligonucleotide (ASO) knockdown strategy targeting FMO3 in LDLRKO (low-density lipoprotein receptor knockout) mice resulted in major reductions in TMAO levels and atherosclerosis, but also showed effects on plasma lipids, insulin, and glucose.

Impact of Individual Traits, Saturated Fat, and Protein Source on the Gut Microbiome.

Interindividual variation in the composition of the human gut microbiome was examined in relation to demographic and anthropometric traits, and to changes in dietary saturated fat intake and protein source. One hundred nine healthy men and women aged 21 to 65, with BMIs of 18 to 36, were randomized, after a two-week baseline diet, to high (15% total energy [E])- or low (7%E)-saturated-fat groups and randomly received three diets (four weeks each) in which the protein source (25%E) was mainly red meat (beef, pork) (12%E), white meat (chicken, turkey) (12%E), and nonmeat sources (nuts, beans, soy) (16%E). Taxonomic characterization using 16S ribosomal DNA was performed on fecal samples collected at each diet completion.

GAW20: methods and strategies for the new frontiers of epigenetics and pharmacogenomics.

GAW20 provided a platform for developing and evaluating statistical methods to analyze human lipid-related phenotypes, DNA methylation, and single-nucleotide markers in a study involving a pharmaceutical intervention. In this article, we present an overview of the data sets and the contributions analyzing these data. The data, donated by the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) investigators, included data from 188 families ( = 1105) which included genome-wide DNA methylation data before and after a 3-week treatment with fenofibrate, single-nucleotide polymorphisms, metabolic syndrome components before and after treatment, and a variety of covariates.

Detecting responses to treatment with fenofibrate in pedigrees.

Background: Fenofibrate (Fb) is a known treatment for elevated triglyceride (TG) levels. The Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study was designed to investigate potential contributors to the effects of Fb on TG levels. Here, we summarize the analyses of 8 papers whose authors had access to the GOLDN data and were grouped together because they pursued investigations into Fb treatment responses as part of GAW20.

Author Correction: Integration of human adipocyte chromosomal interactions with adipose gene expression prioritizes obesity-related genes from GWAS.

In the original version of this Article, Supplementary Table 10 contained incorrect primer sequences for the mobility shift assay for SNP rs4776984. These errors have now been fixed and the corrected version of the Supplementary Information PDF is available to download from the HTML version of the Article.

DMD genotype correlations from the Duchenne Registry: Endogenous exon skipping is a factor in prolonged ambulation for individuals with a defined mutation subtype.

Antisense oligonucleotide (AON)-mediated exon skipping is an emerging therapeutic for individuals with Duchenne muscular dystrophy (DMD). Skipping of exons adjacent to common exon deletions in DMD using AONs can produce in-frame transcripts and functional protein. Targeted skipping of DMD exons 8, 44, 45, 50, 51, 52, 53, and 55 is predicted to benefit 47% of affected individuals.

Repurposing Dantrolene for Long-Term Combination Therapy to Potentiate Antisense-Mediated DMD Exon Skipping in the mdx Mouse.

Duchenne muscular dystrophy (DMD) is caused by mutations in DMD, resulting in loss of dystrophin, which is essential to muscle health. DMD "exon skipping" uses anti-sense oligo-nucleotides (AONs) to force specific exon exclusion during mRNA processing to restore reading frame and rescue of partially functional dystrophin protein. Although exon-skipping drugs in humans show promise, levels of rescued dystrophin protein remain suboptimal.

Transcriptome analysis in whole blood reveals increased microbial diversity in schizophrenia.

The role of the human microbiome in health and disease is increasingly appreciated. We studied the composition of microbial communities present in blood across 192 individuals, including healthy controls and patients with three disorders affecting the brain: schizophrenia, amyotrophic lateral sclerosis, and bipolar disorder. By using high-quality unmapped RNA sequencing reads as candidate microbial reads, we performed profiling of microbial transcripts detected in whole blood.

A Strategy for Discovery of Endocrine Interactions with Application to Whole-Body Metabolism.

Inter-tissue communication via secreted proteins has been established as a vital mechanism for proper physiologic homeostasis. Here, we report a bioinformatics framework using a mouse reference population, the Hybrid Mouse Diversity Panel (HMDP), which integrates global multi-tissue expression data and publicly available resources to identify and functionally annotate novel circuits of tissue-tissue communication. We validate this method by showing that we can identify known as well as novel endocrine factors responsible for communication between tissues.

Integration of human adipocyte chromosomal interactions with adipose gene expression prioritizes obesity-related genes from GWAS.

Increased adiposity is a hallmark of obesity and overweight, which affect 2.2 billion people world-wide. Understanding the genetic and molecular mechanisms that underlie obesity-related phenotypes can help to improve treatment options and drug development.

Diet1, bile acid diarrhea, and FGF15/19: mouse model and human genetic variants.

Diet1 modulates intestinal production of the hormone, fibroblast growth factor (FGF)15, which signals in liver to regulate bile acid synthesis. C57BL/6ByJ mice with a spontaneous -null mutation are resistant to hypercholesterolemia compared with wild-type C57BL/6J mice through enhanced cholesterol conversion to bile acids. To further characterize the role of Diet1 in metabolism, we generated mice on the C57BL/6J genetic background.

Genetic variation and gene expression across multiple tissues and developmental stages in a nonhuman primate.

By analyzing multitissue gene expression and genome-wide genetic variation data in samples from a vervet monkey pedigree, we generated a transcriptome resource and produced the first catalog of expression quantitative trait loci (eQTLs) in a nonhuman primate model. This catalog contains more genome-wide significant eQTLs per sample than comparable human resources and identifies sex- and age-related expression patterns. Findings include a master regulatory locus that likely has a role in immune function and a locus regulating hippocampal long noncoding RNAs (lncRNAs), whose expression correlates with hippocampal volume.

Family-specific aggregation of lipid GWAS variants confers the susceptibility to familial hypercholesterolemia in a large Austrian family.

Background And Aims: Hypercholesterolemia confers susceptibility to cardiovascular disease (CVD). Both serum total cholesterol (TC) and LDL-cholesterol (LDL-C) exhibit a strong genetic component (heritability estimates 0.41-0.

Diet, gonadal sex, and sex chromosome complement influence white adipose tissue miRNA expression.

Background: MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression by targeting specific mRNA species for degradation or interfering with translation. Specific miRNAs are key regulators of adipogenesis, and are expressed at different levels in adipose tissue from lean and obese mice. The degree of lipid accumulation and distribution of white adipose tissue differs between males and females, and it is unknown whether sex differences in adipose tissue-specific miRNA expression may contribute to this dimorphism.

Genetic complexity at expression quantitative trait loci.

Background: Identifying variants that regulate gene expression and delineating their genetic architecture is a critical next step in our endeavors to better understand the genetic etiology of complex diseases. The appropriate genomic tools are in place, and preliminary analytic strategies have been developed.

Methods: Here we used Genetic Analysis Workshop (GAW) 19 data to investigate the genetic complexity of expression quantitative trait loci (eQTL), chromosomal regions likely to harbor regulatory elements responsible for gene expression.