Microbiome-wide association studies on large population cohorts have highlighted associations between the gut microbiome and complex traits, including type 2 diabetes (T2D) and obesity
. However, the ...causal relationships remain largely unresolved. We leveraged information from 952 normoglycemic individuals for whom genome-wide genotyping, gut metagenomic sequence and fecal short-chain fatty acid (SCFA) levels were available
, then combined this information with genome-wide-association summary statistics for 17 metabolic and anthropometric traits. Using bidirectional Mendelian randomization (MR) analyses to assess causality
, we found that the host-genetic-driven increase in gut production of the SCFA butyrate was associated with improved insulin response after an oral glucose-tolerance test (P = 9.8 × 10
), whereas abnormalities in the production or absorption of another SCFA, propionate, were causally related to an increased risk of T2D (P = 0.004). These data provide evidence of a causal effect of the gut microbiome on metabolic traits and support the use of MR as a means to elucidate causal relationships from microbiome-wide association findings.
Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes ...from the 1000 Genomes Project, we report a GWAS meta-analysis of ~185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
To explore novel genetic loci for diabetic nephropathy, we performed genome-wide association studies (GWAS) for diabetic nephropathy in Japanese patients with type 2 diabetes. We analyzed the ...association of 5,768,242 single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes, 2,380 nephropathy cases and 5,234 controls. We further performed GWAS for diabetic nephropathy using independent Japanese patients with type 2 diabetes, 429 cases and 358 controls and the results of these two GWAS were combined with an inverse variance meta-analysis (stage-1), followed by a de novo genotyping for the candidate SNP loci (p < 1.0 × 10(-4)) in an independent case-control study (Stage-2; 1,213 cases and 1,298 controls). After integrating stage-1 and stage-2 data, we identified one SNP locus, significantly associated with diabetic nephropathy; rs56094641 in FTO, P = 7.74 × 10(-10). We further examined the association of rs56094641 with diabetic nephropathy in independent Japanese patients with type 2 diabetes (902 cases and 1,221 controls), and found that the association of this locus with diabetic nephropathy remained significant after integrating all association data (P = 7.62 × 10(-10)). We have identified FTO locus as a novel locus for conferring susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes.
Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including ...type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P < 5 × 10
). Overall, approximately 15% of variance in BW was captured by assays of fetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (R
= -0.22, P = 5.5 × 10
), T2D (R
= -0.27, P = 1.1 × 10
) and coronary artery disease (R
= -0.30, P = 6.5 × 10
). In addition, using large -cohort datasets, we demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P = 1.9 × 10
). We demonstrate that life-course associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and identify some of the pathways through which these causal genetic effects are mediated.
The genetics of diabetic complications Ahlqvist, Emma; van Zuydam, Natalie R; Groop, Leif C ...
Nature reviews. Nephrology,
05/2015, Volume:
11, Issue:
5
Journal Article
Peer reviewed
The rising global prevalence of diabetes mellitus is accompanied by an increasing burden of morbidity and mortality that is attributable to the complications of chronic hyperglycaemia. These ...complications include blindness, renal failure and cardiovascular disease. Current therapeutic options for chronic hyperglycaemia reduce, but do not eradicate, the risk of these complications. Success in defining new preventative and therapeutic strategies hinges on an improved understanding of the molecular processes involved in the development of these complications. This Review explores the role of human genetics in delivering such insights, and describes progress in characterizing the sequence variants that influence individual predisposition to diabetic kidney disease, retinopathy, neuropathy and accelerated cardiovascular disease. Numerous risk variants for microvascular complications of diabetes have been reported, but very few have shown robust replication. Furthermore, only limited evidence exists of a difference in the repertoire of risk variants influencing macrovascular disease between those with and those without diabetes. Here, we outline the challenges associated with the genetic analysis of diabetic complications and highlight ongoing efforts to deliver biological insights that can drive translational benefits.
Purpose of Review
The increased cardiovascular disease (CVD) risk in subjects with type 2 diabetes (T2D) is well established. This review collates the available evidence and assesses the shared ...genetic background between T2D and CVD: the causal contribution of common risk factors to T2D and CVD and how genetics can be used to improve drug development and clinical outcomes.
Recent Findings
Large-scale genome-wide association studies (GWAS) of T2D and CVD support a shared genetic background but minimal individual locus overlap.
Summary
Mendelian randomisation (MR) analyses show that T2D is causal for CVD, but GWAS of CVD, T2D and their common risk factors provided limited evidence for individual locus overlap. Distinct but functionally related pathways were enriched for CVD and T2D genetic associations reflecting the lack of locus overlap and providing some explanation for the variable associations of common risk factors with CVD and T2D from MR analyses.
Ornithine transcarbamylase deficiency (OTCD) is a monogenic disease of ammonia metabolism in hepatocytes. Severe disease is frequently treated by orthotopic liver transplantation. An attractive ...approach is the correction of a patient’s own cells to regenerate the liver with gene-repaired hepatocytes. This study investigates the efficacy and safety of ex vivo correction of primary human hepatocytes. Hepatocytes isolated from an OTCD patient were genetically corrected ex vivo, through the deletion of a mutant intronic splicing site achieving editing efficiencies >60% and the restoration of the urea cycle in vitro. The corrected hepatocytes were transplanted into the liver of FRGN mice and repopulated to high levels (>80%). Animals transplanted and liver repopulated with genetically edited patient hepatocytes displayed normal ammonia, enhanced clearance of an ammonia challenge and OTC enzyme activity, as well as lower urinary orotic acid when compared to mice repopulated with unedited patient hepatocytes. Gene expression was shown to be similar between mice transplanted with unedited or edited patient hepatocytes. Finally, a genome-wide screening by performing CIRCLE-seq and deep sequencing of >70 potential off-targets revealed no unspecific editing. Overall analysis of disease phenotype, gene expression, and possible off-target editing indicated that the gene editing of a severe genetic liver disease was safe and effective.
Display omitted
The study describes the preclinical investigation of the ex vivo gene editing of hepatocytes isolated from a patient with severe liver disease. The results reveal that gene editing is safe and effective in actual disease-affected human liver cells both in vitro and in vivo in liver-humanized mice.
Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in ...the contexts of diabetes and smoking status.
We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status.
We identified 5 genome-wide significant (
≤5×10
) associations with PAD in 449 548 (N
=12 086) individuals of European ancestry near
) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the
) locus was associated with PAD (odds ratio 95% CI, 1.51 1.32-1.74,
=2.5×10
,
=5.3×10
). Furthermore, in smokers, rs12910984 at the
locus was associated with PAD (odds ratio 95% CI, 1.15 1.11-1.19,
=9.3×10
,
=3.9×10
).
Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.
Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide ...association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
IMPORTANCE: Neuropathic pain (NP) has important clinical and socioeconomic consequences for individuals and society. Increasing evidence indicates that genetic factors make a significant contribution ...to NP, but genome-wide association studies (GWASs) are scant in this field and could help to elucidate susceptibility to NP. OBJECTIVE: To identify genetic variants associated with NP susceptibility. DESIGN, SETTING, AND PARTICIPANTS: This genetic association study included a meta-analysis of GWASs of NP using 3 independent cohorts: ie, Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS); Generation Scotland: Scottish Family Health Study (GS:SFHS); and the United Kingdom Biobank (UKBB). Data analysis was conducted from April 2018 to December 2019. EXPOSURES: Individuals with NP (ie, case participants; those with pain of ≥3 months’ duration and a Douleur Neuropathique en 4 Questions score ≥3) and individuals with no pain (ie, control participants) with or without diabetes from GoDARTS and GS:SFHS were identified using validated self-completed questionnaires. In the UKBB, self-reported prescribed medication and hospital records were used as a proxy to identify case participants (patients recorded as receiving specific anti-NP medicines) and control participants. MAIN OUTCOMES AND MEASURES: GWAS was performed using linear mixed modeling. GWAS summary statistics were combined using fixed-effect meta-analysis. A total of 51 variants previously shown to be associated with NP were tested for replication. RESULTS: This study included a total of 4512 case participants (2662 58.9% women; mean SD age, 61.7 10.8 years) and 428 489 control participants (227 817 53.2% women; mean SD age, 62.3 11.5 years) in the meta-analysis of 3 cohorts with European descent. The study found a genome-wide significant locus at chromosome 12q23.1, which mapped to SLC25A3 (rs369920026; odds ratio OR for having NP, 1.68; 95% CI, 1.40-2.02; P = 1.30 × 10−8), and a suggestive variant at 13q14.2 near CAB39L (rs7992766; OR, 1.09; 95% CI, 1.05-1.14; P = 1.22 × 10−7). These mitochondrial phosphate carriers and calcium binding genes are expressed in brain and dorsal root ganglia. Colocalization analyses using expression quantitative loci data found that the suggestive variant was associated with expression of CAB39L in the brain cerebellum (P = 1.01 × 10−14). None of the previously reported variants were replicated. CONCLUSIONS AND RELEVANCE: To our knowledge, this was the largest meta-analyses of GWAS to date. It found novel genetic variants associated with NP susceptibility. These findings provide new insights into the genetic architecture of NP and important information for further studies.
PDF
