Loss of transient receptor potential channel 5 causes obesity and postpartum depression.

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care.

The Genetic Basis of Metabolic Disease.

Recent developments in genetics and genomics are providing a detailed and systematic characterization of the genetic underpinnings of common metabolic diseases and traits, highlighting the inherent complexity within systems for homeostatic control and the many ways in which that control can fail. The genetic architecture underlying these common metabolic phenotypes is complex, with each trait influenced by hundreds of loci spanning a range of allele frequencies and effect sizes. Here, we review the growing appreciation of this complexity and how this has fostered the implementation of genome-scale approaches that deliver robust mechanistic inference and unveil new strategies for translational exploitation.

Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance.

Hypothalamic melanocortin neurons play a pivotal role in weight regulation. Here, we examined the contribution of Semaphorin 3 (SEMA3) signaling to the development of these circuits. In genetic studies, we found 40 rare variants in SEMA3A-G and their receptors (PLXNA1-4; NRP1-2) in 573 severely obese individuals; variants disrupted secretion and/or signaling through multiple molecular mechanisms. Rare variants in this set of genes were significantly enriched in 982 severely obese cases compared to 4,449 controls. In a zebrafish mutagenesis screen, deletion of 7 genes in this pathway led to increased somatic growth and/or adiposity demonstrating that disruption of Semaphorin 3 signaling perturbs energy homeostasis. In mice, deletion of the Neuropilin-2 receptor in Pro-opiomelanocortin neurons disrupted their projections from the arcuate to the paraventricular nucleus, reduced energy expenditure, and caused weight gain. Cumulatively, these studies demonstrate that SEMA3-mediated signaling drives the development of hypothalamic melanocortin circuits involved in energy homeostasis.

KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation.

Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.

Genomics of disease risk in globally diverse populations.

Risk of disease is multifactorial and can be shaped by socio-economic, demographic, cultural, environmental and genetic factors. Our understanding of the genetic determinants of disease risk has greatly advanced with the advent of genome-wide association studies (GWAS), which detect associations between genetic variants and complex traits or diseases by comparing populations of cases and controls. However, much of this discovery has occurred through GWAS of individuals of European ancestry, with limited representation of other populations, including from Africa, The Americas, Asia and Oceania. Population demography, genetic drift and adaptation to environments over thousands of years have led globally to the diversification of populations. This global genomic diversity can provide new opportunities for discovery and translation into therapies, as well as a better understanding of population disease risk. Large-scale multi-ethnic and representative biobanks and population health resources provide unprecedented opportunities to understand the genetic determinants of disease on a global scale.

Author Correction: Genomics of disease risk in globally diverse populations.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Obesity-Associated GNAS Mutations and the Melanocortin Pathway.

BACKGROUND: GNAS encodes the Gαs (stimulatory G-protein alpha subunit) protein, which mediates G protein-coupled receptor (GPCR) signaling. GNAS mutations cause developmental delay, short stature, and skeletal abnormalities in a syndrome called Albright's hereditary osteodystrophy. Because of imprinting, mutations on the maternal allele also cause obesity and hormone resistance (pseudohypoparathyroidism). METHODS: We performed exome sequencing and targeted resequencing in 2548 children who presented with severe obesity, and we unexpectedly identified 22 GNAS mutation carriers. We investigated whether the effect of GNAS mutations on melanocortin 4 receptor (MC4R) signaling explains the obesity and whether the variable clinical spectrum in patients might be explained by the results of molecular assays. RESULTS: Almost all GNAS mutations impaired MC4R signaling. A total of 6 of 11 patients who were 12 to 18 years of age had reduced growth. In these patients, mutations disrupted growth hormone-releasing hormone receptor signaling, but growth was unaffected in carriers of mutations that did not affect this signaling pathway (mean standard-deviation score for height, -0.90 vs. 0.75, respectively; P = 0.02). Only 1 of 10 patients who reached final height before or during the study had short stature. GNAS mutations that impaired thyrotropin receptor signaling were associated with developmental delay and with higher thyrotropin levels (mean [±SD], 8.4±4.7 mIU per liter) than those in 340 severely obese children who did not have GNAS mutations (3.9±2.6 mIU per liter; P = 0.004). CONCLUSIONS: Because pathogenic mutations may manifest with obesity alone, screening of children with severe obesity for GNAS deficiency may allow early diagnosis, improving clinical outcomes, and melanocortin agonists may aid in weight loss. GNAS mutations that are identified by means of unbiased genetic testing differentially affect GPCR signaling pathways that contribute to clinical heterogeneity. Monogenic diseases are clinically more variable than their classic descriptions suggest. (Funded by Wellcome and others.).

Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila.

The discovery of human obesity-associated genes can reveal new mechanisms to target for weight loss therapy. Genetic studies of obese individuals and the analysis of rare genetic variants can identify novel obesity-associated genes. However, establishing a functional relationship between these candidate genes and adiposity remains a significant challenge. We uncovered a large number of rare homozygous gene variants by exome sequencing of severely obese children, including those from consanguineous families. By assessing the function of these genes in vivo in Drosophila, we identified 4 genes, not previously linked to human obesity, that regulate adiposity (itpr, dachsous, calpA, and sdk). Dachsous is a transmembrane protein upstream of the Hippo signalling pathway. We found that 3 further members of the Hippo pathway, fat, four-jointed, and hippo, also regulate adiposity and that they act in neurons, rather than in adipose tissue (fat body). Screening Hippo pathway genes in larger human cohorts revealed rare variants in TAOK2 associated with human obesity. Knockdown of Drosophila tao increased adiposity in vivo demonstrating the strength of our approach in predicting novel human obesity genes and signalling pathways and their site of action.

The impact of population-level HbA1c screening on reducing diabetes diagnostic delay in middle-aged adults: a UK Biobank analysis.

AIMS/HYPOTHESIS: Screening programmes can detect cases of undiagnosed diabetes earlier than symptomatic or incidental diagnosis. However, the improvement in time to diagnosis achieved by screening programmes compared with routine clinical care is unclear. We aimed to use the UK Biobank population-based study to provide the first population-based estimate of the reduction in time to diabetes diagnosis that could be achieved by HbA1c-based screening in middle-aged adults. METHODS: We studied UK Biobank participants aged 40-70 years with HbA1c measured at enrolment (but not fed back to participants/clinicians) and linked primary and secondary healthcare data (n=179,923) and identified those with a pre-existing diabetes diagnosis (n=13,077, 7.3%). Among the remaining participants (n=166,846) without a diabetes diagnosis, we used an elevated enrolment HbA1c level (≥48 mmol/mol [≥6.5%]) to identify those with undiagnosed diabetes. For this group, we used Kaplan-Meier analysis to assess the time between enrolment HbA1c measurement and subsequent clinical diabetes diagnosis up to 10 years, and Cox regression to identify clinical factors associated with delayed diabetes diagnosis. RESULTS: In total, 1.0% (1703/166,846) of participants without a diabetes diagnosis had undiagnosed diabetes based on calibrated HbA1c levels at UK Biobank enrolment, with a median HbA1c level of 51.3 mmol/mol (IQR 49.1-57.2) (6.8% [6.6-7.4]). These participants represented an additional 13.0% of diabetes cases in the study population relative to the 13,077 participants with a diabetes diagnosis. The median time to clinical diagnosis for those with undiagnosed diabetes was 2.2 years, with a median HbA1c at clinical diagnosis of 58.2 mmol/mol (IQR 51.0-80.0) (7.5% [6.8-9.5]). Female participants with lower HbA1c and BMI measurements at enrolment experienced the longest delay to clinical diagnosis. CONCLUSIONS/INTERPRETATION: Our population-based study shows that HbA1c screening in adults aged 40-70 years can reduce the time to diabetes diagnosis by a median of 2.2 years compared with routine clinical care. The findings support the use of HbA1c screening to reduce the time for which individuals are living with undiagnosed diabetes.

The influence of rare variants in circulating metabolic biomarkers.

Circulating metabolite levels are biomarkers for cardiovascular disease (CVD). Here we studied, association of rare variants and 226 serum lipoproteins, lipids and amino acids in 7,142 (discovery plus follow-up) healthy participants. We leveraged the information from multiple metabolite measurements on the same participants to improve discovery in rare variant association analyses for gene-based and gene-set tests by incorporating correlated metabolites as covariates in the validation stage. Gene-based analysis corrected for the effective number of tests performed, confirmed established associations at APOB, APOC3, PAH, HAL and PCSK (p<1.32x10-7) and identified novel gene-trait associations at a lower stringency threshold with ACSL1, MYCN, FBXO36 and B4GALNT3 (p<2.5x10-6). Regulation of the pyruvate dehydrogenase (PDH) complex was associated for the first time, in gene-set analyses also corrected for effective number of tests, with IDL and LDL parameters, as well as circulating cholesterol (pMETASKAT<2.41x10-6). In conclusion, using an approach that leverages metabolite measurements obtained in the same participants, we identified novel loci and pathways involved in the regulation of these important metabolic biomarkers. As large-scale biobanks continue to amass sequencing and phenotypic information, analytical approaches such as ours will be useful to fully exploit the copious amounts of biological data generated in these efforts.