Publications by authors named "Kuang Lin"

75 Publications

A novel flameless oxidation and in-chamber melting system coupled with advanced scrubbers for a laboratory waste plant.

Waste Manag 2021 May 18;126:706-718. Epub 2021 Apr 18.

Environmental Resource and Management Research Center, National Cheng Kung University, Tainan 70101, Taiwan; Department of Resource Engineering, National Cheng Kung University, Tainan 70101, Taiwan.

This is the first study integrate the flameless oxidation (FO) and in-chamber melting (ICM) processes in a primary chamber of a laboratory waste incinerator to improve energy and emission performances. Two liquid burners created a twin-cyclonic fluid field that achieved the FO and ICM in the same chamber. The first cyclone provided a well-mixed and lower temperature FO to reduce auxiliary diesel consumption, NOx and PM emissions by 25.8%, 30.9%, and 79.2%, respectively, from the original system. The hot gases produced by FO enhance the ICM process and transformed the bottom ashes to stabler slags, in turn meeting the regulations for nonhazardous wastes. The other cyclone enhanced the drying and water-gas shift reaction in the drying zone by recirculating the CO and enthalpy from FO and ICM. Eventually, the residual CO, hydrocarbons, and H were sent to the secondary chamber for further oxidation. A computational fluid dynamic simulation supported the fluid field assumption posed in this study. Moreover, advanced scrubbers were employed after thermal treatments to reduce HCl and SO by 81.8% and 38.8% and further retarded the corrosion rate in the baghouse supporting cage by 87.7%. The precursors of condensable particulate matter were reduced by condensation and finally removed in the baghouse. Nevertheless, the emissions of the high- and mid-molecular-weight polycyclic aromatic hydrocarbons were greatly reduced by 60.8-93.1% and 80.2-99.9%, respectively. Consequently, the new system reduced annual emissions by 40.7-87.6% and operating costs by 41.5%, allowing recovery of the remodification investment in 20.5 months.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wasman.2021.03.043DOI Listing
May 2021

A large-scale genome-wide association analysis of lung function in the Chinese population identifies novel loci and highlights shared genetic etiology with obesity.

Eur Respir J 2021 Mar 25. Epub 2021 Mar 25.

Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

Lung function is a heritable complex phenotype with obesity being one of its important risk factors. However, the knowledge of their shared genetic basis is limited. Most genome-wide association studies (GWASs) for lung function have been based on European populations, limiting the generalisability across populations. Large-scale lung function GWAS in other populations are lacking.We included 100 285 subjects from China Kadoorie Biobank (CKB). To identify novel loci for lung function, single-trait GWAS were performed on FEV1, FVC, FEV1/FVC in CKB. We then performed genome-wide cross-trait analysis between the lung function and obesity traits (body mass index [BMI], BMI-adjusted waist-to-hip ratio, and BMI-adjusted waist circumference) to investigate the shared genetic effects in CKB. Finally, polygenic risk scores (PRSs) of lung function were developed in CKB and its interaction with BMI's association on lung function were examined. We also conducted cross-trait analysis in parallel with CKB using 457 756 subjects from UK Biobank (UKB) for replication and investigation of ancestry specific effect.We identified 9 genome-wide significant novel loci for FEV1, 6 for FVC and 3 for FEV1/FVC in CKB. FEV1 and FVC showed significant negative genetic correlation with obesity traits in both CKB and UKB. Genetic loci shared between lung function and obesity traits highlighted important pathways, including cell proliferation, embryo and tissue development. Mendelian randomisation analysis suggested significant negative causal effect of BMI on FEV1 and on FVC in both CKB and UKB. Lung function PRSs significantly modified the effect of change-in-BMI on change-in-lung function during an average follow-up of 8 years.This large-scale GWAS of lung function identified novel loci and shared genetic etiology between lung function and obesity. Change-in-BMI might affect change-in-lung function differently according to a subject's polygenic background. These findings may open new avenue for the development of molecular-targeted therapies for obesity and lung function improvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/13993003.00199-2021DOI Listing
March 2021

Improved prediction of fracture risk leveraging a genome-wide polygenic risk score.

Genome Med 2021 Feb 3;13(1):16. Epub 2021 Feb 3.

Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Room H-413, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec, H3T 1E2, Canada.

Background: Accurately quantifying the risk of osteoporotic fracture is important for directing appropriate clinical interventions. While skeletal measures such as heel quantitative speed of sound (SOS) and dual-energy X-ray absorptiometry bone mineral density are able to predict the risk of osteoporotic fracture, the utility of such measurements is subject to the availability of equipment and human resources. Using data from 341,449 individuals of white British ancestry, we previously developed a genome-wide polygenic risk score (PRS), called gSOS, that captured 25.0% of the total variance in SOS. Here, we test whether gSOS can improve fracture risk prediction.

Methods: We examined the predictive power of gSOS in five genome-wide genotyped cohorts, including 90,172 individuals of European ancestry and 25,034 individuals of Asian ancestry. We calculated gSOS for each individual and tested for the association between gSOS and incident major osteoporotic fracture and hip fracture. We tested whether adding gSOS to the risk prediction models had added value over models using other commonly used clinical risk factors.

Results: A standard deviation decrease in gSOS was associated with an increased odds of incident major osteoporotic fracture in populations of European ancestry, with odds ratios ranging from 1.35 to 1.46 in four cohorts. It was also associated with a 1.26-fold (95% confidence interval (CI) 1.13-1.41) increased odds of incident major osteoporotic fracture in the Asian population. We demonstrated that gSOS was more predictive of incident major osteoporotic fracture (area under the receiver operating characteristic curve (AUROC) = 0.734; 95% CI 0.727-0.740) and incident hip fracture (AUROC = 0.798; 95% CI 0.791-0.805) than most traditional clinical risk factors, including prior fracture, use of corticosteroids, rheumatoid arthritis, and smoking. We also showed that adding gSOS to the Fracture Risk Assessment Tool (FRAX) could refine the risk prediction with a positive net reclassification index ranging from 0.024 to 0.072.

Conclusions: We generated and validated a PRS for SOS which was associated with the risk of fracture. This score was more strongly associated with the risk of fracture than many clinical risk factors and provided an improvement in risk prediction. gSOS should be explored as a tool to improve risk stratification to identify individuals at high risk of fracture.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-021-00838-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860212PMC
February 2021

The genetic architecture of sporadic and multiple consecutive miscarriage.

Nat Commun 2020 11 25;11(1):5980. Epub 2020 Nov 25.

University of Queensland, St Lucia, QLD, Australia.

Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P = 3.2 × 10, odds ratio (OR) = 1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF = 6.4%, P = 1.3 × 10, OR = 1.7; rs143445068, MAF = 0.8%, P = 5.2 × 10, OR = 3.4; rs183453668, MAF = 0.5%, P = 2.8 × 10, OR = 3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-19742-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689465PMC
November 2020

Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.

Nat Genet 2020 12 16;52(12):1303-1313. Epub 2020 Nov 16.

Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-020-00725-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116530PMC
December 2020

Genome-wide transcriptome analysis identifies novel dysregulated genes implicated in Alzheimer's pathology.

Alzheimers Dement 2020 09 5;16(9):1213-1223. Epub 2020 Aug 5.

Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana.

Introduction: Abnormal gene expression patterns may contribute to the onset and progression of late-onset Alzheimer's disease (LOAD).

Methods: We performed transcriptome-wide meta-analysis (N = 1440) of blood-based microarray gene expression profiles as well as neuroimaging and cerebrospinal fluid (CSF) endophenotype analysis.

Results: We identified and replicated five genes (CREB5, CD46, TMBIM6, IRAK3, and RPAIN) as significantly dysregulated in LOAD. The most significantly altered gene, CREB5, was also associated with brain atrophy and increased amyloid beta (Aβ) accumulation, especially in the entorhinal cortex region. cis-expression quantitative trait loci mapping analysis of CREB5 detected five significant associations (P < 5 × 10 ), where rs56388170 (most significant) was also significantly associated with global cortical Aβ deposition measured by [ F]Florbetapir positron emission tomography and CSF Aβ .

Discussion: RNA from peripheral blood indicated a differential gene expression pattern in LOAD. Genes identified have been implicated in biological processes relevant to Alzheimer's disease. CREB, in particular, plays a key role in nervous system development, cell survival, plasticity, and learning and memory.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/alz.12092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541709PMC
September 2020

Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study.

Mol Psychiatry 2020 Jul 27. Epub 2020 Jul 27.

The Centre for Neuroimaging & Cognitive Genomics (NICOG) and NCBES Galway Neuroscience Centre, National University of Ireland Galway, Galway, Ireland.

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-020-0820-7DOI Listing
July 2020

Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics.

Sci Transl Med 2020 06;12(549)

Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK.

Inhibition of sclerostin is a therapeutic approach to lowering fracture risk in patients with osteoporosis. However, data from phase 3 randomized controlled trials (RCTs) of romosozumab, a first-in-class monoclonal antibody that inhibits sclerostin, suggest an imbalance of serious cardiovascular events, and regulatory agencies have issued marketing authorizations with warnings of cardiovascular disease. Here, we meta-analyze published and unpublished cardiovascular outcome trial data of romosozumab and investigate whether genetic variants that mimic therapeutic inhibition of sclerostin are associated with higher risk of cardiovascular disease. Meta-analysis of up to three RCTs indicated a probable higher risk of cardiovascular events with romosozumab. Scaled to the equivalent dose of romosozumab (210 milligrams per month; 0.09 grams per square centimeter of higher bone mineral density), the genetic variants were associated with lower risk of fracture and osteoporosis (commensurate with the therapeutic effect of romosozumab) and with a higher risk of myocardial infarction and/or coronary revascularization and major adverse cardiovascular events. The same variants were also associated with increased risk of type 2 diabetes mellitus and higher systolic blood pressure and central adiposity. Together, our findings indicate that inhibition of sclerostin may elevate cardiovascular risk, warranting a rigorous evaluation of the cardiovascular safety of romosozumab and other sclerostin inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aay6570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116615PMC
June 2020

Identification of type 2 diabetes loci in 433,540 East Asian individuals.

Nature 2020 06 6;582(7811):240-245. Epub 2020 May 6.

Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D); however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2263-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292783PMC
June 2020

Dysregulated Fc gamma receptor-mediated phagocytosis pathway in Alzheimer's disease: network-based gene expression analysis.

Neurobiol Aging 2020 04 10;88:24-32. Epub 2019 Dec 10.

Department of Radiology and Imaging Sciences, and the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address:

Transcriptomics has become an important tool for identification of biological pathways dysregulated in Alzheimer's disease (AD). We performed a network-based gene expression analysis of blood-based microarray gene expression profiles using 2 independent cohorts, Alzheimer's Disease Neuroimaging Initiative (ADNI; N = 661) and AddNeuroMed (N = 674). Weighted gene coexpression network analysis identified 17 modules from ADNI and 13 from AddNeuroMed. Four of the modules derived in ADNI were significantly related to AD; 5 modules in AddNeuroMed were significant. Gene-set enrichment analysis of the AD-related modules identified and replicated 3 biological pathways including the Fc gamma receptor-mediated phagocytosis pathway. Module-based association analysis showed the AD-related module, which has the 3 pathways, to be associated with cognitive function and neuroimaging biomarkers. Gene-based association analysis identified PRKCD in the Fc gamma receptor-mediated phagocytosis pathway as being significantly associated with cognitive function and cerebrospinal fluid biomarkers. The identification of the Fc gamma receptor-mediated phagocytosis pathway implicates the peripheral innate immune system in the pathophysiology of AD. PRKCD is known to be related to neurodegeneration induced by amyloid-β.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2019.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085455PMC
April 2020

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

The transferability of lipid loci across African, Asian and European cohorts.

Nat Commun 2019 09 24;10(1):4330. Epub 2019 Sep 24.

Department of Human Genetics, Wellcome Sanger Institute, Hinxton, CB10 1SA, UK.

Most genome-wide association studies are based on samples of European descent. We assess whether the genetic determinants of blood lipids, a major cardiovascular risk factor, are shared across populations. Genetic correlations for lipids between European-ancestry and Asian cohorts are not significantly different from 1. A genetic risk score based on LDL-cholesterol-associated loci has consistent effects on serum levels in samples from the UK, Uganda and Greece (r = 0.23-0.28, p < 1.9 × 10). Overall, there is evidence of reproducibility for ~75% of the major lipid loci from European discovery studies, except triglyceride loci in the Ugandan samples (10% of loci). Individual transferable loci are identified using trans-ethnic colocalization. Ten of fourteen loci not transferable to the Ugandan population have pleiotropic associations with BMI in Europeans; none of the transferable loci do. The non-transferable loci might affect lipids by modifying food intake in environments rich in certain nutrients, which suggests a potential role for gene-environment interactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-12026-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760173PMC
September 2019

Genetic Predisposition to Type 2 Diabetes and Risk of Subclinical Atherosclerosis and Cardiovascular Diseases Among 160,000 Chinese Adults.

Diabetes 2019 11 9;68(11):2155-2164. Epub 2019 Aug 9.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.

In observational studies, type 2 diabetes is associated with two- to fourfold higher risk of cardiovascular diseases (CVD). Using data from the China Kadoorie Biobank (CKB), we examined associations of genetically predicted type 2 diabetes with CVD among ∼160,000 participants to assess whether these relationships are causal. A type 2 diabetes genetic risk score (comprising 48 established risk variants) was associated with the presence of carotid plaque (odds ratio 1.17 [95% CI 1.05, 1.29] per 1 unit higher log-odds of type 2 diabetes; = 6,819) and elevated risk of ischemic stroke (IS) (1.08 [1.02, 1.14]; = 17,097), nonlacunar IS (1.09 [1.03, 1.16]; = 13,924), and major coronary event (1.12 [1.02, 1.23]; = 5,081). There was no significant association with lacunar IS (1.03 [0.91, 1.16], = 3,173) or intracerebral hemorrhage (ICH) (1.01 [0.94, 1.10], = 6,973), although effect estimates were imprecise. These associations were consistent with observational associations of type 2 diabetes with CVD in CKB ( for heterogeneity >0.3) and with the associations of type 2 diabetes with IS, ICH, and coronary heart disease in two-sample Mendelian randomization analyses based on summary statistics from European population genome-wide association studies ( for heterogeneity >0.2). In conclusion, among Chinese adults, genetic predisposition to type 2 diabetes was associated with atherosclerotic CVD, consistent with a causal association.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db19-0224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804628PMC
November 2019

Follicle-stimulating hormone promotes renal tubulointerstitial fibrosis in aging women via the AKT/GSK-3β/β-catenin pathway.

Aging Cell 2019 10 26;18(5):e12997. Epub 2019 Jun 26.

Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Estrogen withdrawal in aging women contributes to the progression of chronic kidney disease (CKD). However, the effect of high circulating follicle-stimulating hormone (FSH) levels on renal dysfunction remains unknown. In this study, blood samples from 3,055 postmenopausal women were collected and tested, which showed that there was a strong negative correlation between eGFR and FSH levels (p < 0.001), independent of LH, testosterone, and estradiol. Functional FSHR was detected in renal tubular epithelial cells. In vivo, high circulating FSH levels promoted a phenotype of tubulointerstitial fibrosis, characterized by increases in 24-hr urine protein/creatinine ratio, serum Cr, serum BUN, and ECM deposition. Similar results obtained from cultured HK-2 cells showed that FSH increased the transcriptional and protein expression of profibrotic mediators (collagen IV, fibronectin, and PAI-1). This promotion of fibrosis by FSH occurred through the activation of AKT/GSK-3β/β-catenin pathway, which could be attenuated by silencing FSHR by siRNA or by LY294002 or MK2206. In addition, FSH-stimulated HK-2 cells secreted IL-8, which promoted macrophage migration to exacerbate tubulointerstitial fibrosis. These results revealed a previously unknown effect of FSH on kidney injury, which may offer a critical insight into the development of CKD in aging postmenopausal women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/acel.12997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718534PMC
October 2019

New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries.

Nat Genet 2019 03 25;51(3):481-493. Epub 2019 Feb 25.

Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0321-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397078PMC
March 2019

Metabolomic consequences of genetic inhibition of PCSK9 compared with statin treatment.

Circulation 2018 11 15;138(22):2499-2512. Epub 2018 Aug 15.

Diabetes and Obesity Research Program, University of Helsinki, Helsinki, Finland.

Background: Both statins and PCSK9 inhibitors lower blood low-density lipoprotein cholesterol (LDL-C) levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these two lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial.

Methods: 228 circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5,359 individuals (2,659 on treatment) in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial at 6-months post-randomization. The corresponding metabolic measures were analyzed in eight population cohorts (N=72,185) using rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors.

Results: Scaled to an equivalent lowering of LDL-C, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (=0.88). Alterations in lipoprotein lipid composition and fatty acid distribution were similar. However, discrepancies were observed for very-low-density lipoprotein (VLDL) lipid measures. For instance, genetic inhibition of PCSK9 had weaker effects on lowering of VLDL-cholesterol compared with statin therapy (54% vs. 77% reduction, relative to the lowering effect on LDL-C; =2x10 for heterogeneity). Genetic inhibition of PCSK9 showed no significant effects on amino acids, ketones, or a marker of inflammation (GlycA) whereas statin treatment weakly lowered GlycA levels.

Conclusions: Genetic inhibition of PCSK9 had similar metabolic effects to statin therapy on detailed lipid and metabolite profiles. However, PCSK9 inhibitors are predicted to have weaker effects on VLDL lipids compared with statins for an equivalent lowering of LDL-C, which potentially translate into smaller reductions in cardiovascular disease risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254781PMC
November 2018

Metabolomic Consequences of Genetic Inhibition of PCSK9 Compared With Statin Treatment

Circulation 2018 Nov;138(22):2499–2512

Diabetes and Obesity Research Program, University of Helsinki, Finland

Background: Both statins and proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitors lower blood low-density lipoprotein cholesterol levels to reduce risk of cardiovascular events. To assess potential differences between metabolic effects of these 2 lipid-lowering therapies, we performed detailed lipid and metabolite profiling of a large randomized statin trial and compared the results with the effects of genetic inhibition of PCSK9, acting as a naturally occurring trial.

Methods: Two hundred twenty-eight circulating metabolic measures were quantified by nuclear magnetic resonance spectroscopy, including lipoprotein subclass concentrations and their lipid composition, fatty acids, and amino acids, for 5359 individuals (2659 on treatment) in the PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) trial at 6 months postrandomization. The corresponding metabolic measures were analyzed in 8 population cohorts (N=72 185) using PCSK9 rs11591147 as an unconfounded proxy to mimic the therapeutic effects of PCSK9 inhibitors.

Results: Scaled to an equivalent lowering of low-density lipoprotein cholesterol, the effects of genetic inhibition of PCSK9 on 228 metabolic markers were generally consistent with those of statin therapy (R2=0.88). Alterations in lipoprotein lipid composition and fatty acid distribution were similar. However, discrepancies were observed for very-low-density lipoprotein lipid measures. For instance, genetic inhibition of PCSK9 had weaker effects on lowering of very-low-density lipoprotein cholesterol compared with statin therapy (54% versus 77% reduction, relative to the lowering effect on low-density lipoprotein cholesterol; P=2×10-7 for heterogeneity). Genetic inhibition of PCSK9 showed no significant effects on amino acids, ketones, or a marker of inflammation (GlycA), whereas statin treatment weakly lowered GlycA levels.

Conclusions: Genetic inhibition of PCSK9 had similar metabolic effects to statin therapy on detailed lipid and metabolite profiles. However, PCSK9 inhibitors are predicted to have weaker effects on very-low-density lipoprotein lipids compared with statins for an equivalent lowering of low-density lipoprotein cholesterol, which potentially translate into smaller reductions in cardiovascular disease risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.118.034942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254781PMC
November 2018

Interethnic analyses of blood pressure loci in populations of East Asian and European descent.

Nat Commun 2018 11 28;9(1):5052. Epub 2018 Nov 28.

Tohoku Medical Megabank Organization, Tohoku University, Sendai, 980-8573, Japan.

Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP (max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-07345-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261994PMC
November 2018

Genomic Analyses from Non-invasive Prenatal Testing Reveal Genetic Associations, Patterns of Viral Infections, and Chinese Population History.

Cell 2018 10;175(2):347-359.e14

BGI-Shenzhen, Shenzhen 518083, Guangdong, China.

We analyze whole-genome sequencing data from 141,431 Chinese women generated for non-invasive prenatal testing (NIPT). We use these data to characterize the population genetic structure and to investigate genetic associations with maternal and infectious traits. We show that the present day distribution of alleles is a function of both ancient migration and very recent population movements. We reveal novel phenotype-genotype associations, including several replicated associations with height and BMI, an association between maternal age and EMB, and between twin pregnancy and NRG1. Finally, we identify a unique pattern of circulating viral DNA in plasma with high prevalence of hepatitis B and other clinically relevant maternal infections. A GWAS for viral infections identifies an exceptionally strong association between integrated herpesvirus 6 and MOV10L1, which affects piwi-interacting RNA (piRNA) processing and PIWI protein function. These findings demonstrate the great value and potential of accumulating NIPT data for worldwide medical and genetic analyses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2018.08.016DOI Listing
October 2018

Low Temperature Oxidation Kinetics of Biodiesel Molecules: Rate Rules for Concerted HO Elimination from Alkyl Ester Peroxy Radicals.

J Phys Chem A 2018 Oct 11;122(42):8259-8273. Epub 2018 Oct 11.

International University, Vietnam National University-HCMC , Ho Chi Minh City , Vietnam.

In an attempt to construct detailed kinetic mechanisms for biodiesel fuels on the fly, high-pressure rate rules for the concerted HO elimination reaction class were derived using a comprehensive training reaction set of more than 60 reactions involving different alkyl methyl/ethyl ester peroxy radicals (RCOOR')-OO. Using the composite electronic structure method CBS-QB3 in combination with classical statistical mechanics and the transition state theory (TST) rate model, high-pressure rate constants for the reactions in the training set as well as thermodynamic properties for the species involved were calculated. The corrections from Eckart tunneling and hindered internal rotation (HIR) treatments were also included in the calculations. The results reveal that the ester group (-COO-) selectively promotes the reaction when compared with the traditional hydrocarbon fuels; thus it is recommended that the seven derived rate rules for the title reaction class (including the thermodynamic data of the species involved in the NASA format) should be used for construction of detailed kinetic mechanisms for real biodiesel molecules.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jpca.8b05070DOI Listing
October 2018

Use of schizophrenia and bipolar disorder polygenic risk scores to identify psychotic disorders.

Br J Psychiatry 2018 09;213(3):535-541

Division of Psychiatry and Institute of Cognitive Neuroscience,University College London and Institute of Psychiatry, Psychology and Neuroscience, King's College London and South London and Maudsley NHS Foundation Trust,UK.

Background: There is increasing evidence for shared genetic susceptibility between schizophrenia and bipolar disorder. Although genetic variants only convey subtle increases in risk individually, their combination into a polygenic risk score constitutes a strong disease predictor.AimsTo investigate whether schizophrenia and bipolar disorder polygenic risk scores can distinguish people with broadly defined psychosis and their unaffected relatives from controls.

Method: Using the latest Psychiatric Genomics Consortium data, we calculated schizophrenia and bipolar disorder polygenic risk scores for 1168 people with psychosis, 552 unaffected relatives and 1472 controls.

Results: Patients with broadly defined psychosis had dramatic increases in schizophrenia and bipolar polygenic risk scores, as did their relatives, albeit to a lesser degree. However, the accuracy of predictive models was modest.

Conclusions: Although polygenic risk scores are not ready for clinical use, it is hoped that as they are refined they could help towards risk reduction advice and early interventions for psychosis.Declaration of interestR.M.M. has received honoraria for lectures from Janssen, Lundbeck, Lilly, Otsuka and Sunovian.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1192/bjp.2018.89DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130805PMC
September 2018

Differential expression of mRNA and miRNA in guinea pigs following infection with HSV2v.

Exp Ther Med 2017 Sep 19;14(3):2577-2583. Epub 2017 Jul 19.

Dermatological Department, The Second Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410005, P.R. China.

MicroRNAs (miRNAs) are 22-nucleotide single-stranded RNAs which regulate gene expression by targeting 3' untranslated regions. Previous studies have suggested that miRNAs may be used as markers for investigating the molecular regulation of gene expression. In the present study, miRNA and mRNA expression profiles were investigated using a massively parallel next generation sequencing technique to compare herpes simplex virus (HSV)2-infected (n=3) and healthy (n=3) epithelial tissues from guinea pigs. Total RNA was isolated and RNA sequencing was performed using a HiSeq 2000 sequencing system. Differential expression of miRNA and mRNA was analyzed using two-tailed t-tests. A negative correlation was detected between the miRNAs and their predicted target genes. Following infection with HSV2, 205 and 159 miRNAs were demonstrated to be upregulated and downregulated, respectively. These differentially expressed miRNAs were associated with cellular and metabolic processes, biological regulation, response to stimuli and cellular components of the immune system, as determined by functional gene ontology analysis. Following HSV2 infection, 6 upregulated miRNAs including miR-592, miR-1245b-5p, miR-150, miR-342-5p, miR-1245b-3p and miR-124 were demonstrated to participate in the toll-like receptor (TLR) pathway by targeting related genes. These results suggested that the downregulated genes were associated with the TLR pathway after infection with HSV2. The results of reverse transcription-quantitative polymerase chain reaction analysis were consistent with RNA sequencing, indicating that the increased expression of these miRNAs downregulated the TLR pathway-associated genes, which may mediate the progression of HSV2-induced genital herpes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/etm.2017.4815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609232PMC
September 2017

A polygenic risk score analysis of psychosis endophenotypes across brain functional, structural, and cognitive domains.

Am J Med Genet B Neuropsychiatr Genet 2018 Jan 29;177(1):21-34. Epub 2017 Aug 29.

Institute of Psychiatry Psychology and Neuroscience at King's College London and South London, Maudsley NHS Foundation Trust, London, UK.

This large multi-center study investigates the relationships between genetic risk for schizophrenia and bipolar disorder, and multi-modal endophenotypes for psychosis. The sample included 4,242 individuals; 1,087 patients with psychosis, 822 unaffected first-degree relatives of patients, and 2,333 controls. Endophenotypes included the P300 event-related potential (N = 515), lateral ventricular volume (N = 798), and the cognitive measures block design (N = 3,089), digit span (N = 1,437), and the Ray Auditory Verbal Learning Task (N = 2,406). Data were collected across 11 sites in Europe and Australia; all genotyping and genetic analyses were done at the same laboratory in the United Kingdom. We calculated polygenic risk scores for schizophrenia and bipolar disorder separately, and used linear regression to test whether polygenic scores influenced the endophenotypes. Results showed that higher polygenic scores for schizophrenia were associated with poorer performance on the block design task and explained 0.2% (p = 0.009) of the variance. Associations in the same direction were found for bipolar disorder scores, but this was not statistically significant at the 1% level (p = 0.02). The schizophrenia score explained 0.4% of variance in lateral ventricular volumes, the largest across all phenotypes examined, although this was not significant (p = 0.063). None of the remaining associations reached significance after correction for multiple testing (with alpha at 1%). These results indicate that common genetic variants associated with schizophrenia predict performance in spatial visualization, providing additional evidence that this measure is an endophenotype for the disorder with shared genetic risk variants. The use of endophenotypes such as this will help to characterize the effects of common genetic variation in psychosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.b.32581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763362PMC
January 2018

Kinetics of Thermal Unimolecular Decomposition of Acetic Anhydride: An Integrated Deterministic and Stochastic Model.

J Phys Chem A 2017 Apr 14;121(16):3028-3036. Epub 2017 Apr 14.

International University, Vietnam National University - HCMC , Quarter 6, Linh Trung Ward, Thu Duc District, Ho Chi Minh City, Vietnam.

An integrated deterministic and stochastic model within the master equation/Rice-Ramsperger-Kassel-Marcus (ME/RRKM) framework was first used to characterize temperature- and pressure-dependent behaviors of thermal decomposition of acetic anhydride in a wide range of conditions (i.e., 300-1500 K and 0.001-100 atm). Particularly, using potential energy surface and molecular properties obtained from high-level electronic structure calculations at CCSD(T)/CBS, macroscopic thermodynamic properties and rate coefficients of the title reaction were derived with corrections for hindered internal rotation and tunneling treatments. Being in excellent agreement with the scattered experimental data, the results from deterministic and stochastic frameworks confirmed and complemented each other to reveal that the main decomposition pathway proceeds via a 6-membered-ring transition state with the 0 K barrier of 35.2 kcal·mol. This observation was further understood and confirmed by the sensitivity analysis on the time-resolved species profiles and the derived rate coefficients with respect to the ab initio barriers. Such an agreement suggests the integrated model can be confidently used for a wide range of conditions as a powerful postfacto and predictive tool in detailed chemical kinetic modeling and simulation for the title reaction and thus can be extended to complex chemical reactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jpca.7b00015DOI Listing
April 2017

Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases: A Mendelian Randomization Study.

JAMA Oncol 2017 May;3(5):636-651

Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.

Importance: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation.

Objective: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases.

Data Sources: Genomewide association studies (GWAS) published up to January 15, 2015.

Study Selection: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available.

Data Extraction And Synthesis: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population.

Main Outcomes And Measures: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation.

Results: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [95% CI, 0.05-0.15]).

Conclusions And Relevance: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2016.5945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5638008PMC
May 2017

Proposed association between the hexanucleotide repeat of C9orf72 and opposability index of the thumb.

Amyotroph Lateral Scler Frontotemporal Degener 2017 05 23;18(3-4):175-181. Epub 2016 Dec 23.

a Department of Basic and Clinical Neurosciences , Maurice Wohl Clinical Neuroscience Institute, King's College London , London , UK and.

Objective: Amyotrophic lateral sclerosis (ALS) is a fatal disease caused by motor neuron and sub-cerebral projection neuron degeneration. We sought to explore the particular susceptibility of humans to neurodegeneration and whether any characteristic human features might predispose to selective vulnerability of the critical motor circuitry in ALS. The pathophysiology of the C9orf72 repeat is not yet understood, despite its role as a common cause of ALS and frontotemporal dementia.

Methods: We examined the development of the monosynaptic cortico-motoneuronal system, key to skilled hand movements, measured by the thumb opposability index, and its relationship to the C9orf72 hexanucleotide repeat expansion, a strong predisposing factor for neurodegeneration, using the genomic tool BLAST.

Results: We found a statistically significant linear relationship between the C9orf72 hexanucleotide bit score, a measure of genomic conservation of the aligned region across different species, and the thumb opposability index (Pearson's correlation coefficient of 0.78, p value 0.023). The C9orf72 hexanucleotide repeat was only found in humans, chimpanzees and gorillas, species with higher opposability indices.

Conclusions: This may support a role of the hexanucleotide repeat in the same developmental pathways in species with higher prehensility, which may be associated with the selective vulnerability of cortico-motoneuronal cells in humans, manifested most obviously as the 'split hand' syndrome in ALS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/21678421.2016.1257024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5425628PMC
May 2017

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

Nat Genet 2016 09 25;48(9):1043-8. Epub 2016 Jul 25.

Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556360PMC
September 2016

Association of a Locus in the CAMTA1 Gene With Survival in Patients With Sporadic Amyotrophic Lateral Sclerosis.

JAMA Neurol 2016 07;73(7):812-20

Academic Neurology Unit, Department of Neuroscience, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, England.

Importance: Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disorder with a poor prognosis and a median survival of 3 years. However, a significant proportion of patients survive more than 10 years from symptom onset.

Objective: To identify gene variants influencing survival in ALS.

Design, Setting, And Participants: This genome-wide association study (GWAS) analyzed survival in data sets from several European countries and the United States that were collected by the Italian Consortium for the Genetics of ALS and the International Consortium on Amyotrophic Lateral Sclerosis Genetics. The study population included 4256 patients with ALS (3125 [73.4%] deceased) with genotype data extended to 7 174 392 variants by imputation analysis. Samples of DNA were collected from January 1, 1993, to December 31, 2009, and analyzed from March 1, 2014, to February 28, 2015.

Main Outcomes And Measures: Cox proportional hazards regression under an additive model with adjustment for age at onset, sex, and the first 4 principal components of ancestry, followed by meta-analysis, were used to analyze data. Survival distributions for the most associated genetic variants were assessed by Kaplan-Meier analysis.

Results: Among the 4256 patients included in the analysis (2589 male [60.8%] and 1667 female [39.2%]; mean [SD] age at onset, 59 [12] years), the following 2 novel loci were significantly associated with ALS survival: at 10q23 (rs139550538; P = 1.87 × 10-9) and in the CAMTA1 gene at 1p36 (rs2412208, P = 3.53 × 10-8). At locus 10q23, the adjusted hazard ratio for patients with the rs139550538 AA or AT genotype was 1.61 (95% CI, 1.38-1.89; P = 1.87 × 10-9), corresponding to an 8-month reduction in survival compared with TT carriers. For rs2412208 CAMTA1, the adjusted hazard ratio for patients with the GG or GT genotype was 1.17 (95% CI, 1.11-1.24; P = 3.53 × 10-8), corresponding to a 4-month reduction in survival compared with TT carriers.

Conclusions And Relevance: This GWAS robustly identified 2 loci at genome-wide levels of significance that influence survival in patients with ALS. Because ALS is a rare disease and prevention is not feasible, treatment that modifies survival is the most realistic strategy. Therefore, identification of modifier genes that might influence ALS survival could improve the understanding of the biology of the disease and suggest biological targets for pharmaceutical intervention. In addition, genetic risk scores for survival could be used as an adjunct to clinical trials to account for the genetic contribution to survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2016.1114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556366PMC
July 2016