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Quantitative changes in leptin concentration lead to alterations in food intake and body weight, but the regulatory mechanisms that control leptin gene expression are poorly understood. Here we report that fat-specific and quantitative leptin expression is controlled by redundant cis elements and trans factors interacting with the proximal promoter together with a long noncoding RNA (lncOb). Diet-induced obese mice lacking lncOb show increased fat mass with reduced plasma leptin levels and lose weight after leptin treatment, whereas control mice do not. Consistent with this finding, large-scale genetic studies of humans reveal a significant association of single-nucleotide polymorphisms (SNPs) in the region of human lncOb with lower plasma leptin levels and obesity. These results show that reduced leptin gene expression can lead to a hypoleptinemic, leptin-responsive form of obesity and provide a framework for elucidating the pathogenic mechanism in the subset of obese patients with low endogenous leptin levels.Defects in the regulation of leptin gene expression can lead to a hypoleptinemic, leptin-responsive form of obesity.

Melanocortin 4 receptor (MC4R) deficiency, caused by mutations in MC4R, is the most common cause of monogenic forms of obesity. However, these mutations have often been identified in small-scale, case-focused studies. Here, we assess the penetrance of previously reported MC4R mutations at a population level. Furthermore, we examine why some carriers of pathogenic mutations remain of normal weight, to gain insight into the mechanisms that control body weight. We identified 59 known obesity-increasing mutations in MC4R from the Human Gene Mutation Database (HGMD) and Clinvar. We assessed their penetrance and effect on obesity (body mass index [BMI] ≥ 30 kg/m2) in >450,000 individuals (age 40-69 years) of the UK Biobank, a population-based cohort study. Of these 59 mutations, only 11 had moderate-to-high penetrance and increased the odds of obesity by more than 2-fold. We subsequently focused on these 11 mutations and examined differences between carriers of normal weight and carriers with obesity. Twenty-eight of the 182 carriers of these 11 mutations were of normal weight. Body composition of carriers of normal weight was similar to noncarriers of normal weight, whereas among individuals with obesity, carriers had a somewhat higher BMI than noncarriers (1.44 ± 0.07 standard deviation scores [SDSs] ± standard error [SE] versus 1.29 ± 0.001, P = 0.03), because of greater lean mass (1.44 ± 0.09 versus 1.15 ± 0.002, P = 0.002). Carriers of normal weight more often reported that, already at age 10 years, their body size was below average or average (72%) compared with carriers with obesity (48%) (P = 0.01). To assess the polygenic contribution to body weight in carriers of normal weight and carriers with obesity, we calculated a genome-wide polygenic risk score for BMI (PRSBMI). The PRSBMI of carriers of normal weight (PRSBMI = -0.64 ± 0.18) was significantly lower than of carriers with obesity (0.40 ± 0.11; P = 1.7 × 10-6), and tended to be lower than that of noncarriers of normal weight (-0.29 ± 0.003; P = 0.05). Among carriers, those with a low PRSBMI (bottom quartile) have an approximately 5-kg/m2 lower BMI (approximately 14 kg of body weight for a 1.7-m-tall person) than those with a high PRS (top quartile). Because the UK Biobank population is healthier than the general population in the United Kingdom, penetrance may have been somewhat underestimated. We showed that large-scale data are needed to validate the impact of mutations observed in small-scale and case-focused studies. Furthermore, we observed that despite the key role of MC4R in obesity, the effects of pathogenic MC4R mutations may be countered, at least in part, by a low polygenic risk potentially representing other innate mechanisms implicated in body weight regulation.

The purpose of this study is to use a genotype-first approach to explore highly penetrant, autosomal dominant cardiovascular diseases with external features, the RASopathies and Marfan syndrome (MFS), using biobank data. This study uses exome sequencing and corresponding phenotypic data from Mount Sinai’s BioMe (n = 32,344) and the United Kingdom Biobank (UKBB; n = 49,960). Variant curation identified pathogenic/likely pathogenic (P/LP) variants in RASopathy genes and FBN1. Twenty-one subjects harbored P/LP RASopathy variants; three (14%) were diagnosed, and another 46% had ≥1 classic Noonan syndrome (NS) feature. Major NS features (short stature [9.5% p = 7e-5] and heart anomalies [19%, p < 1e-5]) were less frequent than expected. Prevalence of hypothyroidism/autoimmune disorders was enriched compared with biobank populations (p = 0.007). For subjects with FBN1 P/LP variants, 14/41 (34%) had a MFS diagnosis or highly suggestive features. Five of 15 participants (33%) with echocardiographic data had aortic dilation, fewer than expected (p = 8e-6). Ectopia lentis affected only 15% (p < 1e-5). Substantial fractions of individuals harboring P/LP variants with partial or full phenotypic matches to a RASopathy or MFS remain undiagnosed, some not meeting diagnostic criteria. Routine population genotyping would enable multidisciplinary care and avoid life-threatening events.

Background Pathogenic variants in BRCA1 and BRCA2 ( BRCA1/2 ) lead to increased risk of breast, ovarian, and other cancers, but most variant-positive individuals in the general population are unaware of their risk, and little is known about prevalence in non-European populations. We investigated BRCA1/2 prevalence and impact in the electronic health record (EHR)-linked Bio Me Biobank in New York City. Methods Exome sequence data from 30,223 adult Bio Me participants were evaluated for pathogenic variants in BRCA1/2 . Prevalence estimates were made in population groups defined by genetic ancestry and self-report. EHR data were used to evaluate clinical characteristics of variant-positive individuals. Results There were 218 (0.7%) individuals harboring expected pathogenic variants, resulting in an overall prevalence of 1 in 139. The highest prevalence was in individuals with Ashkenazi Jewish (AJ; 1 in 49), Filipino and other Southeast Asian (1 in 81), and non-AJ European (1 in 103) ancestry. Among 218 variant-positive individuals, 112 (51.4%) harbored known founder variants: 80 had AJ founder variants ( BRCA1 c.5266dupC and c.68_69delAG, and BRCA2 c.5946delT), 8 had a Puerto Rican founder variant ( BRCA2 c.3922G>T), and 24 had one of 19 other founder variants. Non-European populations were more likely to harbor BRCA1/2 variants that were not classified in ClinVar or that had uncertain or conflicting evidence for pathogenicity (uncertain/conflicting). Within mixed ancestry populations, such as Hispanic/Latinos with genetic ancestry from Africa, Europe, and the Americas, there was a strong correlation between the proportion of African genetic ancestry and the likelihood of harboring an uncertain/conflicting variant. Approximately 28% of variant-positive individuals had a personal history, and 45% had a personal or family history of BRCA1/2- associated cancers. Approximately 27% of variant-positive individuals had prior clinical genetic testing for BRCA1/2 . However, individuals with AJ founder variants were twice as likely to have had a clinical test (39%) than those with other pathogenic variants (20%). Conclusions These findings deepen our knowledge about BRCA1/2 variants and associated cancer risk in diverse populations, indicate a gap in knowledge about potential cancer-related variants in non-European populations, and suggest that genomic screening in diverse patient populations may be an effective tool to identify at-risk individuals.

Background Population-based genomic screening has the predicted ability to reduce morbidity and mortality associated with medically actionable conditions. However, much research is needed to develop standards for genomic screening and to understand the perspectives of people offered this new testing modality. This is particularly true for non-European ancestry populations who are vastly underrepresented in genomic medicine research. Therefore, we implemented a pilot genomic screening program in the Bio Me Biobank in New York City, where the majority of participants are of non-European ancestry. Methods We initiated genomic screening for well-established genes associated with hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), and familial hypercholesterolemia (FH). We evaluated and included an additional gene ( TTR ) associated with hereditary transthyretin amyloidosis (hATTR), which has a common founder variant in African ancestry populations. We evaluated the characteristics of 74 participants who received results associated with these conditions. We also assessed the preferences of 7461 newly enrolled Bio Me participants to receive genomic results. Results In the pilot genomic screening program, 74 consented participants received results related to HBOC ( N  = 26), LS ( N  = 6), FH ( N  = 8), and hATTR ( N  = 34). Thirty-three of 34 (97.1%) participants who received a result related to hATTR were self-reported African American/African (AA) or Hispanic/Latinx (HL), compared to 14 of 40 (35.0%) participants who received a result related to HBOC, LS, or FH. Among the 7461 participants enrolled after the Bio Me protocol modification to allow the return of genomic results, 93.4% indicated that they would want to receive results. Younger participants, women, and HL participants were more likely to opt to receive results. Conclusions The addition of TTR to a pilot genomic screening program meant that we returned results to a higher proportion of AA and HL participants, in comparison with genes traditionally included in genomic screening programs in the USA. We found that the majority of participants in a multi-ethnic biobank are interested in receiving genomic results for medically actionable conditions. These findings increase knowledge about the perspectives of diverse research participants on receiving genomic results and inform the broader implementation of genomic medicine in underrepresented patient populations.

Microglia are the resident immune cells of the central nervous system and are involved in brain development, homeostasis, and disease. New imaging and genomics technologies are revealing microglial complexity across developmental and functional states, brain regions, and diseases. We curated a set of publicly available gene expression datasets from human microglia spanning disease and health to identify sets of genes reflecting physiological and pathological microglial states. We also integrated multiple human microglial single-cell RNA-seq datasets in Alzheimer’s disease (AD), multiple sclerosis (MS), and Parkinson’s disease, and identified a distinct microglial transcriptional signature shared across diseases. Analysis of germ-line DNA identified genes with variants associated with AD and MS that are overrepresented in microglial gene sets, including the disease-associated transcriptional signature. This work points to genes that are dysregulated in disease states and provides a resource for the analysis of diseases in which microglia are implicated by genetic evidence. Analysis of human microglia across health and disease identifies key gene sets in neurodegeneration, offering insights into their role in CNS disorders.

Background Anxiety and depression display frequent comorbidity. Individuals with comorbid disorders also often have more extreme symptomatology than those with single disorders. This correlation between comorbidity and severity poses an interesting question: Are comorbid forms of anxiety and depression essentially just more severe versions of the pure disorders? Methods In a large major depression (MD) case–control sample of individuals from the China, Oxford and VCU Experimental Research on Genetic Epidemiology project, we examined the patterns of lifetime anxiety comorbidity (including generalized anxiety disorder—GAD, panic disorder, and five phobia subtypes) among MD cases (N = 5,864) in this population. Binary and multinomial logistic regression was used to estimate associations between risk factors and outcomes including MD as well as latent class membership, which were compared using continuation ratios. Results We found a five‐class solution to fit best, and each resulting class had a distinct pattern of association with the tested risk factors. The use of continuation ratios suggests that a class characterized by high endorsement of GAD is comparable to a more severely affected “pure MD” group. The other three classes (characterized by agoraphobia, various specific phobias, and by high endorsement of all comorbid anxiety disorders, respectively) appear to differ meaningfully from MD alone. Conclusions Risk for MD resulting from environmental and psychosocial factors may also predispose individuals to GAD, and less consistently, other anxiety disorders. Presentations of MD with certain phobias display distinguishably different patterns of risk, however, and are therefore likely qualitatively distinct.

Understanding the factors that contribute to behavioral traits is a complex task, and partitioning variance into latent genetic and environmental components is a useful beginning, but it should not also be the end. Many constructs are influenced by their contextual milieu, and accounting for background effects (such as gene–environment correlation) is necessary to avoid bias. This study introduces a method for examining the interplay between traits, in a longitudinal design using differential items in sibling pairs. The model is validated via simulation and power analysis, and we conclude with an application to paternal praise and ADHD symptoms in a twin sample. The model can help identify what type of genetic and environmental interplay may contribute to the dynamic relationship between traits using a cross-lagged panel framework. Overall, it presents a way to estimate and explicate the developmental interplay between a set of traits, free from many common sources of bias.

[...]relative to those with the same level of religiosity in childhood as in adulthood, a 2-unit decrease in religiosity was associated with an increased odds ratio of 1.62 (95% Confidence Interval: 1.16-2.27) for use of illicit drugs; similarly, a 2-unit increase in religiosity from childhood to adulthood was associated with an odds ratio of 1.92 (95% C.I.: 1.51-2.44) for illicit drug use.

Enlargement of the aorta is an important risk factor for aortic aneurysm and dissection, a leading cause of morbidity in the developed world. Here we performed automated extraction of ascending aortic diameter from cardiac magnetic resonance images of 36,021 individuals from the UK Biobank, followed by genome-wide association. We identified lead variants across 41 loci, including genes related to cardiovascular development ( HAND2 , TBX20 ) and Mendelian forms of thoracic aortic disease ( ELN , FBN1 ). A polygenic score significantly predicted prevalent risk of thoracic aortic aneurysm and the need for surgical intervention for patients with thoracic aneurysm across multiple ancestries within the UK Biobank, FinnGen, the Penn Medicine Biobank and the Million Veterans Program (MVP). Additionally, we highlight the primary causal role of blood pressure in reducing aortic dilation using Mendelian randomization. Overall, our findings provide a roadmap for using genetic determinants of human anatomy to understand cardiovascular development while improving prediction of diseases of the thoracic aorta. Trans-ancestry genome-wide analyses identify multiple loci associated with ascending aortic diameter. A polygenic score constructed from these loci predicted prevalent risk of thoracic aortic aneurysm in independent populations.