Polygenic prediction of body mass index and obesity through the life course and across ancestries.

Polygenic scores (PGSs) for body mass index (BMI) may guide early prevention and targeted treatment of obesity. Using genetic data from up to 5.1 million people (4.

Immune, Developmental, and Synaptic Pathways Define Bipolar Disorder Clinical Heterogeneity.

Importance: The clinical heterogeneity of bipolar disorder (BD) is a major obstacle to improving diagnosis, predicting patient outcomes, and developing personalized treatments. A genetic approach is needed to deconstruct the disorder and uncover its fundamental biology. Previous genetic studies focusing on broad diagnostic categories have been limited in their ability to parse this complexity.

Predicting adolescent disordered eating and behaviours: exploring environmental moderators of polygenic risk.

Background: Both genetic and environmental factors contribute to the risk of developing disordered eating, with twin studies demonstrating environmental factors moderate genetic susceptibility. To date, gene-environment interactions leveraging polygenic risk scores (PRS) have not been studied in disordered eating phenotypes beyond anorexia nervosa (AN). This study investigated if polygenic risk for AN interacts with established environmental eating disorder risk factors (parental expectations, parental criticism, parental conflict, parental care and weight-related peer teasing) to predict overall levels of disordered eating in the general population or specific lifetime disordered eating behaviours (avoidance of eating, objective bulimic episodes, self-induced vomiting and driven exercise).

Halving of Australian children's naevus counts 1992-2016 and change in sun behaviour.

Background: In Australia, the lifetime risk of cutaneous melanoma is the highest in the world. The most important melanoma risk factor is the number of acquired cutaneous melanocytic nevi (AMN) on a person, the majority of these forming in adolescence. Childhood exposure to ultraviolet (UV) light is a strong determinant of nevus count.

Hepatic Inactivation of Carnitine Palmitoyltransferase 1a Lowers ApoB-Containing Lipoproteins in Mice.

Background: Genome- and epigenome-wide association studies have associated variants and methylation status of CPT1a (carnitine palmitoyltransferase 1a) to reductions in VLDL (very low-density lipoprotein) cholesterol and triglyceride levels. The objective of this study was to determine the mechanisms by which CPT1a-dependent mitochondrial fatty acid oxidation influences hepatic and lipoprotein metabolism.

Methods: Eight-week-old male and female -floxed mice () and -floxed mice expressing the human apo B transgene (/B100) were administered control adeno-associated virus or adeno-associated virus encoding Cre-recombinase under control of a liver-specific promoter (TBG-Cre [thyroxin-binding globulin]).

Genetics of monozygotic twins reveals the impact of environmental sensitivity on psychiatric and neurodevelopmental phenotypes.

Individual sensitivity to environmental exposures may be genetically influenced. This genotype-by-environment interplay implies differences in phenotypic variance across genotypes, but these variants have proven challenging to detect. Genome-wide association studies of monozygotic twin differences are conducted through family-based variance analyses, which are more robust to the systemic biases that impact population-based methods.

Genetic and environmental effects on weight gain from young adulthood to old age and its association with body mass index at early young adulthood: an individual-based pooled analysis of 16 twin cohorts.

Introduction: Genetic factors contribute to weight gain, but how these effects change over adulthood is still unknown. We studied the impact of genetics on BMI change from young adulthood to old age and its relationship with BMI in early young adulthood.

Data And Methods: Data from 16 longitudinal twin cohorts, including 111,370 adults (56% women) and 55,657 complete twin pairs (42% monozygotic), were pooled.

APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses.

Excess lipid droplet (LD) accumulation is implicated in various diseases, including Alzheimer's disease (AD), yet the mechanisms underlying this accumulation remain unclear. Apolipoprotein E (ApoE) is a droplet-associated protein, and its E4 variant confers the greatest genetic risk for late-onset AD while also being linked to increased neuroinflammation and LD accumulation. In this study, we compared the lipid and protein composition of hepatic LDs in targeted replacement mice expressing human E3 (neutral) or E4 (risk variant), under both baseline conditions and following lipopolysaccharide (LPS) administration.

Genome-wide association studies of binge eating behaviour and anorexia nervosa yield insights into the unique and shared biology of eating disorder phenotypes.

Eating disorders -including anorexia nervosa (AN), bulimia nervosa, and binge eating disorder-are clinically distinct but exhibit symptom overlap and diagnostic crossover. Genomic analyses have mostly examined AN. We conducted the first genomic meta-analysis of binge eating behaviour (BE; 39,279 cases, 1,227,436 controls), alongside new analyses of AN (24,223 cases, 1,243,971 controls) and its subtypes (all European ancestries).

Postoperative Stress Accelerates Atherosclerosis through Inflammatory Remodeling of the HDL Proteome and Impaired Reverse Cholesterol Transport.

Background: Over 10 million patients undergoing non-cardiac surgery annually experience major cardiovascular complications within 30 days, many due to destabilized atherosclerotic plaques. Reverse cholesterol transport (RCT), a key pathway for cholesterol removal by HDL and apoA-I, is critical in preventing plaque progression. While surgery-induced inflammation is known to impair HDL function, its effects on RCT and plaque stability remain unclear.

ABCG5 ABCG8-independent mechanisms fail to maintain sterol balance in mice fed a high cholesterol diet.

The ABCG5 ABCG8 (G5G8) sterol transporter opposes the accumulation of dietary xenosterols, but is also the primary mediator of biliary cholesterol secretion in the cholesterol elimination pathway. In humans and in mouse models of disrupted biliary cholesterol secretion, fecal neutral sterols remain constant, indicating the presence of a G5G8-independent mechanism for cholesterol excretion. Transintestinal cholesterol elimination (TICE) is thought to compensate for biliary G5G8 insufficiency.

Associations between common genetic variants and income provide insights about the socio-economic health gradient.

We conducted a genome-wide association study on income among individuals of European descent (N = 668,288) to investigate the relationship between socio-economic status and health disparities. We identified 162 genomic loci associated with a common genetic factor underlying various income measures, all with small effect sizes (the Income Factor). Our polygenic index captures 1-5% of income variance, with only one fourth due to direct genetic effects.

Genomics yields biological and phenotypic insights into bipolar disorder.

Bipolar disorder is a leading contributor to the global burden of disease. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.

alters the lipid droplet proteome and modulates droplet dynamics.

Excess lipid droplet (LD) accumulation is associated with several pathological states, including Alzheimer's disease (AD). However, the mechanism(s) by which changes in LD composition and dynamics contribute to pathophysiology of these disorders remains unclear. Apolipoprotein E (ApoE) is a droplet associated protein with a common risk variant (E4) that confers the largest increase in genetic risk for late-onset AD.

Hepatic Inactivation of Carnitine Palmitoyltransferase 1a Lowers Apolipoprotein B Containing Lipoproteins in Mice.

Unlabelled: Genome- and epigenome-wide association studies have associated variants and methylation status of carnitine palmitoyltransferase 1a (CPT1a) to reductions in very low-density lipoprotein (VLDL) cholesterol and triglyceride levels. We report significant associations between the presence of SNPs and reductions in plasma cholesterol, as well as positive associations between hepatic Cpt1a expression and plasma cholesterol levels across inbred mouse strains. Mechanistic studies show that both wild type and human apolipoprotein B100 (apoB)-transgenic mice with liver-specific deletion of (LKO) display lower circulating apoB levels consistent with reduced LDL-cholesterol (LDL-C) and LDL particle number.

Parkinson's Disease Polygenic Risk Score and Neurological Involvement in Carriers of the FMR1 Premutation Allele: A Case for Genetic Modifier.

Background: Premutation alleles of the FMR1 X-linked gene containing CGG repeat expansions ranging from 55 to 200 are associated with diverse late-onset neurological involvements, including most severe disorder termed Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). It is intriguing that at least one-third of male, and a much lower than predicted from the X-linkage proportion of female carriers are free of this syndrome. This suggests the existence of secondary genetic factors modifying the risk of neurological involvements in these carriers.

Untargeted lipidomics reveals novel HDL metabotypes and lipid-clinical correlates.

Plasma high-density lipoprotein (HDL), originally studied for its role in lipid transport, is now appreciated to have wide-ranging biological functions that become defective during disease. While >200 lipids have collectively been detected in HDL, published HDL lipidomic analyses in different diseases have commonly been targeted to prespecified subsets of lipids. Here, we report the results of untargeted lipidomic analysis of HDL isolated from 101 subjects referred for computed tomographic coronary imaging for whom multiple additional clinical and lipoprotein metadata were measured.

APOA2 increases cholesterol efflux capacity to plasma HDL by displacing the C-terminus of resident APOA1.

The ability of high-density lipoprotein (HDL) to promote cellular cholesterol efflux is a more robust predictor of cardiovascular disease protection than HDL-cholesterol levels in plasma. Previously, we found that lipidated HDL containing both apolipoprotein A-I (APOA1) and A-II (APOA2) promotes cholesterol efflux via the ATP-binding cassette transporter (ABCA1). In the current study, we directly added purified, lipid-free APOA2 to human plasma and found a dose-dependent increase in whole plasma cholesterol efflux capacity.

Anorexia nervosa polygenic risk, beyond diagnoses: relationship with adolescent disordered eating and behaviors in an Australian female twin population.

Background: It is well established that there is a substantial genetic component to eating disorders (EDs). Polygenic risk scores (PRSs) can be used to quantify cumulative genetic risk for a trait at an individual level. Recent studies suggest PRSs for anorexia nervosa (AN) may also predict risk for other disordered eating behaviors, but no study has examined if PRS for AN can predict disordered eating as a global continuous measure.

Role of DOCK8 in cytokine storm syndromes.

Background: Cytokine storm syndromes (CSSs), including hemophagocytic lymphohistiocytosis (HLH), are increasingly recognized as hyperinflammatory states leading to multiorgan failure and death. Familial HLH in infancy results from homozygous genetic defects in perforin-mediated cytolysis by CD8 T lymphocytes and natural killer (NK) cells. Later-onset CSSs are often associated with heterozygous defects in familial HLH genes, but genetic etiologies for most are unknown.

Enhancement of high-density lipoprotein-associated protease inhibitor activity prevents atherosclerosis progression.

Background And Aims: Inflammatory cells within atherosclerotic lesions secrete proteolytic enzymes that contribute to lesion progression and destabilization, increasing the risk for an acute cardiovascular event. Elastase is a serine protease, secreted by macrophages and neutrophils, that may contribute to the development of unstable plaque. We previously reported interaction of endogenous protease-inhibitor proteins with high-density lipoprotein (HDL), including alpha-1-antitrypsin, an inhibitor of elastase.

Gut Microbiome Multi-Omics and Cognitive Function in the Hispanic Community Health Study/Study of Latinos- Investigation of Neurocognitive Aging.

Introduction: conducted a study within the Hispanic Community Health Study/Study of Latinos- Investigation of Neurocognitive Aging (HCHS/SOL-INCA) cohort to examine the association between gut microbiome and cognitive function.

Methods: We analyzed the fecal metagenomes of 2,471 HCHS/SOL-INCA participants to, cross-sectionally, identify microbial taxonomic and functional features associated with global cognitive function. Omnibus (PERMANOVA) and feature-wise analyses (MaAsLin2) were conducted to identify microbiome-cognition associations, and specific microbial species and pathways (Kyoto Encyclopedia of Genes and Genomes (KEGG modules) associated with cognition.