Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in Citrin Deficiency.

Citrin Deficiency (CD) is caused by inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. We discovered that SLC25A13 loss causes accumulation of glycerol-3-phosphate (G3P), which activates carbohydrate response element binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol, and to transcribe key genes of lipogenesis.

Associations of Combined Genetic and Lifestyle Risks with Incident Type 2 Diabetes in the UK Biobank.

Background: Type 2 diabetes (T2D) results from a complex interplay between genetic predisposition and lifestyle factors. Both genetic susceptibility and unhealthy lifestyle are known to be associated with elevated T2D risk. However, their combined effects on T2D risk are not well studied.

Associations between birthweight and preterm birth and the ages at menarche and menopause.

Background: Women who reach menarche and menopause at earlier ages have been shown to be at increased risk for numerous conditions including cardiovascular disease, cancer, depression, and obesity; however, risk factors for earlier ages of menarche and menopause are not fully understood. Therefore, we aimed to perform a retrospective investigation of the associations between a personal birthweight and/or being born preterm and the age of and menarche and menopause and related events in the Women's Health Initiative, a large, racially and ethnically diverse cohort of postmenopausal women.

Methods: At study entry, women reported their birthweight by category (< 6 lbs.

Multi-omics characterization of type 2 diabetes associated genetic variation.

Discerning the mechanisms driving type 2 diabetes (T2D) pathophysiology from genome-wide association studies (GWAS) remains a challenge. To this end, we integrated omics information from 16 multi-tissue and multi-ancestry expression, protein, and metabolite quantitative trait loci (QTL) studies and 46 multi-ancestry GWAS for T2D-related traits with the largest, most ancestrally diverse T2D GWAS to date. Of the 1,289 T2D GWAS index variants, 716 (56%) demonstrated strong evidence of colocalization with a molecular or T2D-related trait, implicating 657 -effector genes, 1,691 distal-effector genes, 731 metabolites, and 43 T2D-related traits.

Preterm birth, birthweight, and subsequent risk for depression.

An individual's birthweight, a marker of exposures, was recently associated with certain psychiatric conditions. However, studies investigating the relationship between an individual's preterm birth status and/or birthweight and risk for depression during adulthood are sparse; we used data from the Women's Health Initiative (WHI) to investigate these potential associations. At study entry, 86,925 postmenopausal women reported their birthweight by category (<6 lbs.

A cross-ancestry genome-wide meta-analysis, fine-mapping, and gene prioritization approach to characterize the genetic architecture of adiponectin.

Previous genome-wide association studies (GWASs) for adiponectin, a complex trait linked to type 2 diabetes and obesity, identified >20 associated loci. However, most loci were identified in populations of European ancestry, and many of the target genes underlying the associations remain unknown. We conducted a cross-ancestry adiponectin GWAS meta-analysis in ≤46,434 individuals from the Metabolic Syndrome in Men (METSIM) cohort and the ADIPOGen and AGEN consortiums.

Association of maternal birth weight and maternal preterm birth with subsequent risk for adverse reproductive outcomes: The Women's Health Initiative.

Background: Advancements in medical technology and pharmacologic interventions have drastically improved survival of infants born preterm and low birth weight, but knowledge regarding the long-term health impacts of these individuals is limited and inconsistent.

Aim: To investigate whether an individual's birthweight or history of being born preterm increases the risk of an adverse reproductive outcome.

Study Design: Nested case-control study within the Women's Health Initiative.

Associations of maternal preterm birth with subsequent risk for type 2 diabetes in women from the women's health initiative.

Preterm birth has been associated with insulin resistance and beta-cell dysfunction, a hallmark characteristic of type 2 diabetes. However, studies investigating the relationship between a personal history of being born preterm and type 2 diabetes are sparse. We sought to investigate the potential association between a personal history of being born preterm and risk for type 2 diabetes in a racially and ethnically diverse population.

Multi-ancestry genome-wide study in >2.5 million individuals reveals heterogeneity in mechanistic pathways of type 2 diabetes and complications.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes. To characterise the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study (GWAS) data from 2,535,601 individuals (39.7% non-European ancestry), including 428,452 T2D cases.

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.

Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches.

Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation.

We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 × 10), which were delineated to 338 distinct association signals.

Identification of genetic effects underlying type 2 diabetes in South Asian and European populations.

South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n = 16,677) and controls (n = 33,856), followed by combined analyses with Europeans (n = 231,420). We identify 21 novel genetic loci for significant association with T2D (P = 4.

Validation of birth certificate and maternal recall of events in labor and delivery with medical records in the Iowa health in pregnancy study.

Background: Epidemiological research of events related to labor and delivery frequently uses maternal interview or birth certificates as a primary method of data collection; however, the validity of these data are rarely confirmed. This study aimed to examine the validity of birth certificate data and maternal interview of maternal demographics and events related to labor and delivery with data abstracted from medical records in a US setting.

Methods: Birth certificate and maternal recall data from the Iowa Health in Pregnancy Study (IHIPS), a population-based case-control study of risk factors for preterm and small-for-gestational age births, were linked to medical record data to assess the validity of events that occurred during labor and delivery along with reported maternal demographics.

The power of genetic diversity in genome-wide association studies of lipids.

Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels, heart disease remains the leading cause of death worldwide. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease.

Birthweight and subsequent risk for thyroid and autoimmune conditions in postmenopausal women.

The objective of this study was to determine the association between birthweight and risk of thyroid and autoimmune conditions in a large sample of postmenopausal women. Baseline data from the Women's Health Initiative (n = 80,806) were used to examine the associations between birthweight category (<6 lbs., 6-7 lbs.

Genetic discovery and risk characterization in type 2 diabetes across diverse populations.

Genomic discovery and characterization of risk loci for type 2 diabetes (T2D) have been conducted primarily in individuals of European ancestry. We conducted a multiethnic genome-wide association study of T2D among 53,102 cases and 193,679 control subjects from African, Hispanic, Asian, Native Hawaiian, and European population groups in the Population Architecture Genomics and Epidemiology (PAGE) and Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortia. In individuals of African ancestry, we discovered a risk variant in the gene (rs11466334, risk allele frequency (RAF) = 6.

Progress in Defining the Genetic Contribution to Type 2 Diabetes in Individuals of East Asian Ancestry.

Purpose Of Review: Prevalence of type 2 diabetes (T2D) and progression of complications differ between worldwide populations. While obesity is a major contributing risk factor, variations in physiological manifestations, e.g.