Abstract
Quantitative trait locus (QTL) mapping of molecular phenotypes such as metabolites, lipids and proteins through genome-wide association studies represents a powerful means of highlighting ...molecular mechanisms relevant to human diseases. However, a major challenge of this approach is to identify the causal gene(s) at the observed QTLs. Here, we present a framework for the 'Prioritization of candidate causal Genes at Molecular QTLs' (ProGeM), which incorporates biological domain-specific annotation data alongside genome annotation data from multiple repositories. We assessed the performance of ProGeM using a reference set of 227 previously reported and extensively curated metabolite QTLs. For 98% of these loci, the expert-curated gene was one of the candidate causal genes prioritized by ProGeM. Benchmarking analyses revealed that 69% of the causal candidates were nearest to the sentinel variant at the investigated molecular QTLs, indicating that genomic proximity is the most reliable indicator of 'true positive' causal genes. In contrast, cis-gene expression QTL data led to three false positive candidate causal gene assignments for every one true positive assignment. We provide evidence that these conclusions also apply to other molecular phenotypes, suggesting that ProGeM is a powerful and versatile tool for annotating molecular QTLs. ProGeM is freely available via GitHub.
Genetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase the risk of cardiovascular and metabolic diseases. However, how changes in individual ...lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies.
We characterised the genetic architecture of the human blood lipidome in 5662 hospital controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) and 13,814 healthy British blood donors from the INTERVAL study. We applied a candidate causal gene prioritisation tool to link the genetic variants associated with each lipid to the most likely causal genes, and Gaussian Graphical Modelling network analysis to identify and illustrate relationships between lipids and genetic loci.
We identified 253 genetic associations with 181 lipids measured using direct infusion high-resolution mass spectrometry in PROMIS, and 502 genetic associations with 244 lipids in INTERVAL. Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, MBOAT7, LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci.
Our findings, generated using a distinctive lipidomics platform in an understudied South Asian population, strengthen and expand the knowledge base of the genetic determinants of lipids and their association with cardiometabolic disease-related loci.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Ovarian cancer (OC) is commonly diagnosed among older women who have comorbidities. This hypothesis‐free phenome‐wide association study (PheWAS) aimed to identify comorbidities associated ...with OC, as well as traits that share a genetic architecture with OC.
Methods
We used data from 181,203 white British female UK Biobank participants and analysed OC and OC subtype‐specific genetic risk scores (OC‐GRS) for an association with 889 diseases and 43 other traits. We conducted PheWAS and colocalization analyses for individual variants to identify evidence for shared genetic architecture.
Results
The OC‐GRS was associated with 10 diseases, and the clear cell OC‐GRS was associated with five diseases at the FDR threshold (p = 5.6 × 10−4). Mendelian randomizaiton analysis (MR) provided robust evidence for the association of OC with higher risk of “secondary malignant neoplasm of digestive systems” (OR 1.64, 95% CI 1.33, 2.02), “ascites” (1.48, 95% CI 1.17, 1.86), “chronic airway obstruction” (1.17, 95% CI 1.07, 1.29), and “abnormal findings on examination of the lung” (1.51, 95% CI 1.22, 1.87). Analyses of lung spirometry measures provided further support for compromised respiratory function. PheWAS on individual OC variants identified five genetic variants associated with other diseases, and seven variants associated with biomarkers (all, p ≤ 4.5 × 10−8). Colocalization analysis identified rs4449583 (from TERT locus) as the shared causal variant for OC and seborrheic keratosis.
Conclusions
OC is associated with digestive and respiratory comorbidities. Several variants affecting OC risk were associated with other diseases and biomarkers, with this study identifying a novel genetic locus shared between OC and skin conditions.
Using a hypothesis‐free phenome‐wide association analysis, we identified common comorbidities of ovarian cancer including digestive and respiratory diseases. We further discovered a shared genetic locus between ovarian cancer and certain diseases including seborrheic keratosis.
Abstract The eighteenth century saw antiquaries taking an increased interest in evidence arising from the Roman occupation of Britain. Sir Richard Colt Hoare explored Wales. From 1793 to 1804, his ...tours follow in the footsteps of Giraldus de Barri. His journals describing the Welsh tours are known, except for the year 1804. These have recently been uncovered at Stourhead. The 1804 tour was taken ‘… with a view to … exploring the Roman Roads and Stations through the Principality’. Colt Hoare's translation of the The Itinerary of Archbishop Baldwin Through Wales , a.d. MCLXXXVIII /by Giraldus de Barri; … , followed in 1806. Comparison of Colt Hoare's journals with his translation of Giraldus' Latin text, which is mostly silent on the Romans, shows how he uses the translation to privilege his observations on Roman Wales.
Background The mesolimbic dopamine system, composed primarily of dopaminergic neurons in the ventral tegmental area that project to striatal structures, is considered to be the key mediator of ...reinforcement-related mechanisms in the brain. Prompted by a genome-wide association meta-analysis implicating the Ras-specific guanine nucleotide-releasing factor 2 ( RASGRF2 ) gene in the regulation of alcohol intake in men, we have recently shown that male Rasgrf2−/− mice exhibit reduced ethanol intake and preference accompanied by a perturbed mesolimbic dopamine system. We therefore propose that these mice represent a valid model to further elucidate the precise genes and mechanisms regulating mesolimbic dopamine functioning. Methods Transcriptomic data from the nucleus accumbens (NAcc) of male Rasgrf2−/− mice and wild-type controls were analyzed by weighted gene coexpression network analysis (WGCNA). We performed follow-up genetic association tests in humans using a sample of male adolescents from the IMAGEN study characterized for binge drinking ( n = 905) and ventral striatal activation during an fMRI reward task ( n = 608). Results The WGCNA analyses using accumbal transcriptomic data revealed 37 distinct “modules,” or functionally related groups of genes. Two of these modules were significantly associated with Rasgrf2 knockout status: M5 ( p < 0.001) and M6 ( p < 0.001). In follow-up translational analyses we found that human orthologues for the M5 module were significantly ( p < 0.01) enriched with genetic association signals for binge drinking in male adolescents. Furthermore, the most significant locus, originating from the EH-domain containing 4 ( EHD4 ) gene ( p < 0.001), was also significantly associated with altered ventral striatal activity in male adolescents performing an fMRI reward task ( pempirical < 0.001). Limitations It was not possible to determine the extent to which the M5 module was dysregulated in Rasgrf2−/− mice by perturbed mesolimbic dopamine signalling or by the loss of Rasgrf2 function in the NAcc. Conclusion Taken together, our findings indicate that the accumbal M5 module, initially identified as being dysregulated in male Rasgrf2−/− mice, is also relevant for human alcohol-related phenotypes potentially through the modulation of reinforcement mechanisms in the NAcc. We therefore propose that the genes comprising this module represent important candidates for further elucidation within the context of alcohol-related phenotypes.
Philippe-Jacques de Loutherbourg (1740-1812) (PI 1, PI 2), a member of I'Academie royale de peinture et de sculpture de Paris, Peintre du Roy de France, fled France in 1771 following a domestic and ...financial scandal. He left his wife and children and came to live in Britain. Soon after arriving in London he was appointed chief scenogra-phcc at he Theatre Royal, Drury Lane, under the management of David Garrick (1717-79). He worked there for 10 years to great acclaim before leaving to create a successful miniature theatre, his Eidophusikon. Meanwhile he continued his easel painting He was elected a member of the Royal Academy in 1781. For a few years in the late 1780s, de Loutherbourg was distracted from his work as an artist, initially by his encounter with the charlatan Count Cagliostro (1743-95) and then by setting himself up as a faith-healer. He married a young English widow, Lucy Corson (c1745-1828) in 1774 and from 1783 they lived in Hammersmith until de Loutherbourg died in 1812.
Genomic atlas of the human plasma proteome Sun, Benjamin B; Maranville, Joseph C; Peters, James E ...
Nature (London),
06/2018, Letnik:
558, Številka:
7708
Journal Article
Recenzirano
Odprti dostop
Although plasma proteins have important roles in biological processes and are the direct targets of many drugs, the genetic factors that control inter-individual variation in plasma protein levels ...are not well understood. Here we characterize the genetic architecture of the human plasma proteome in healthy blood donors from the INTERVAL study. We identify 1,927 genetic associations with 1,478 proteins, a fourfold increase on existing knowledge, including trans associations for 1,104 proteins. To understand the consequences of perturbations in plasma protein levels, we apply an integrated approach that links genetic variation with biological pathway, disease, and drug databases. We show that protein quantitative trait loci overlap with gene expression quantitative trait loci, as well as with disease-associated loci, and find evidence that protein biomarkers have causal roles in disease using Mendelian randomization analysis. By linking genetic factors to diseases via specific proteins, our analyses highlight potential therapeutic targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.
Bipolar disorder (BPD) is a debilitating mood disorder with an unclear etiology. A better understanding of the underlying pathophysiological mechanisms will help to identify novel targets for ...improved treatment options and prevention strategies. In this metabolome-wide Mendelian randomization study, we screened for metabolites that may have a causal role in BPD.
We tested a total of 913 circulating metabolite exposures assessed in 14,296 Europeans using a mass spectrometry-based platform. For the BPD outcome, we used summary data from the largest and most recent genome-wide association study reported to date, including 41,917 BPD cases.
We identified 33 metabolites associated with BPD (padjusted < 5.48 × 10−5). Most of them were lipids, including arachidonic acid (β = −0.154, SE = 0.023, p = 3.30 × 10−11), a polyunsaturated omega-6 fatty acid, along with several complex lipids containing either an arachidonic or a linoleic fatty acid side chain. These associations did not extend to other closely related psychiatric disorders like schizophrenia or depression, although they may be involved in the regulation of lithium response. These lipid associations were driven by genetic variants within the FADS1/2/3 gene cluster, which is a robust BPD risk locus encoding a family of fatty acid desaturase enzymes that are responsible for catalyzing the conversion of linoleic acid into arachidonic acid. Statistical colocalization analyses indicated that 27 of the 33 metabolites shared the same genetic etiology with BPD at the FADS1/2/3 cluster, demonstrating that our findings are not confounded by linkage disequilibrium.
Overall, our findings support the notion that arachidonic acid and other polyunsaturated fatty acids may represent potential targets for BPD.
The therapeutic response to lithium in patients with bipolar disorder is highly variable and has a polygenic basis. Genome-wide association studies investigating lithium response have identified ...several relevant loci, though the precise mechanisms driving these associations are poorly understood. We aimed to prioritise the most likely effector gene and determine the mechanisms underlying an intergenic lithium response locus on chromosome 21 identified by the International Consortium on Lithium Genetics (ConLi+Gen).
We conducted in-silico functional analyses by integrating and synthesising information from several publicly available functional genetic datasets and databases including the Genotype-Tissue Expression (GTEx) project and HaploReg.
The findings from this study highlighted TMPRSS15 as the most likely effector gene at the ConLi+Gen lithium response locus. TMPRSS15 encodes enterokinase, a gastrointestinal enzyme responsible for converting trypsinogen into trypsin and thus aiding digestion. Convergent findings from gene-based lookups in human and mouse databases as well as co-expression network analyses of small intestinal RNA-seq data (GTEx) implicated TMPRSS15 in the regulation of intestinal nutrient absorption, including ions like sodium and potassium, which may extend to lithium.
Although the findings from this study indicated that TMPRSS15 was the most likely effector gene at the ConLi+Gen lithium response locus, the evidence was circumstantial. Thus, the conclusions from this study need to be validated in appropriately designed wet-lab studies.
The findings from this study are consistent with a model whereby TMPRSS15 impacts the efficacy of lithium treatment in patients with bipolar disorder by modulating intestinal lithium absorption.
•TMPRSS15 is a novel regulator of lithium response in patients with bipolar disorder.•It is the most likely effector gene at a known lithium response locus.•The gene encodes enterokinase (ENTK), a key modulator of intestinal absorption.•ENTK likely impacts lithium response through the modulation of lithium absorption.
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