Cross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis

Benyamin, Beben; He, Ji; Zhao, Qiongyi; Gratten, Jacob; Garton, Fleur; Leo, Paul; Liu, Zhijun; Mangelsdorf, Marie; Al‐Chalabi, Ammar; Anderson, Lisa K.; Butler, Timothy; Chen, Lu; Chen, Xiang Ding; Cremin, Katie; Deng, Hong Weng; Devine, Matthew; Edson, Janette; Fifita, Jennifer A.; Furlong, Sarah; Han, Ying; Harris, Jessica; Henders, Anjali K.; Jeffree, Rosalind L.; Jin, Zi; Li, Zhongshan; Li, Ting; Li, Mengmeng; Lin, Yong; Liu, Xiaolu; Marshall, Mhairi; McCann, Emma; Mowry, Bryan; Ngo, Shyuan T.; Pamphlett, Roger; Ran, Shu; Reutens, David C.; Rowe, Dominic B.; Sachdev, Perminder S.; Shah, Sonia; Song, Sharon; Tan, Li Jun; Tang, Lu; Berg, Leonard H. van den; Rheenen, Wouter van; Veldink, Jan H.; Wallace, Robyn H.; Wheeler, Lawrie; Williams, Kelly L.; Wu, Jinyu; Wu, Xin; Yang, Jian; Yue, Weihua; Zhang, Zong Hong; Zhang, Dai; Noakes, Peter G.; Blair, Ian P.; Henderson, Robert D.; McCombe, Pamela A.; Visscher, Peter M.; Xu, Huji; Bartlett, Perry F.; Brown, Matthew A.; Wray, Naomi R.; Fan, Dongsheng

doi:10.1038/s41467-017-00471-1

Cited by 93 publications

(102 citation statements)

References 44 publications

(69 reference statements)

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“…To do so, we performed an additional Mendelian randomization study using another set of 75 instruments obtained from an East Asian BMI GWAS up to 158,284 individuals (Table S4 and Supplementary Text S2) [52]. The corresponding summary statistics of ALS for these instruments were extracted from an East Asian ALS GWAS up to 4,084 individuals (1,234 cases and 2,850 controls) (Supplementary Text S2) [56]. The two sets of index SNPs of BMI from the two populations share only one common instrument (i.e.…”

Section: Methodsmentioning

confidence: 99%

Association between premorbid body mass index and amyotrophic lateral sclerosis: causal inference through genetic approaches

Zeng

2019

Preprint

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19Background: Inverse association between premorbid body mass index (BMI) and 20 amyotrophic lateral sclerosis (ALS) has been discovered in observational studies; 21 however, whether this association is causal remains largely unknown. 22 Methods: We employed a two-sample Mendelian randomization approach to evaluate 23 the causal relationship of genetically increased BMI with the risk of ALS. The 24 analyses were implemented using summary statistics obtained for the independent 25 instruments identified from large-scale genome-wide association studies of BMI (up 26 to ~770,000 individuals) and ALS (up to ~81,000 individuals). The causal relationship 27 between BMI and ALS was estimated using inverse-variance weighted methods and 28 was further validated through extensive complementary and sensitivity analyses. 29Findings: Using 1,031 instruments strongly related to BMI, the causal effect of per 30 one standard deviation increase of BMI was estimated to be 1.04 (95% CI 0.97~1.11, 31 p=0.275) in the European population. The null association between BMI and ALS 32 discovered in the European population also held in the East Asian population and was 33 robust against various modeling assumptions and outlier biases. Additionally, the 34 Egger-regression and MR-PRESSO ruled out the possibility of horizontal pleiotropic 35 effects of instruments. 36 Interpretation: Our results do not support the causal role of genetically increased or 37 decreased BMI on the risk of ALS. 38 Key words 39 Body mass index, Amyotrophic lateral sclerosis, Mendelian randomization, 40 Instrumental variable, Genome-wide association studies 41 3/23 1. Introduction 42 Amyotrophic lateral sclerosis (ALS) is a frequent adult-onset fatal neurodegenerative 43 disease clinically characterized by rapidly progressive motor neurons degeneration 44 and death because of respiratory failure [1]. Although great advance has been made 45for the understanding of ALS in the past decades, the pathogenic mechanism 46 underlying ALS remains largely unknown and only few therapeutic options can be 47 50 development of ALS [5, 6, 7, 8, 9, 10, 11]. However, no replicable and definitive 51 environmental risk factors are currently well established for ALS. In addition, due to 52 the quickly growing ageing of the population in the upcoming years, it is evaluated 53 that the number of ALS cases across globe will increase by about 70% [12], which is 54 anticipated to result in rather serious socioeconomic and health burden. Therefore, 55 understanding the risk factors of ALS for improving the medical intervention and 56 quality of life for ALS patients is considerably important from both disease treatment 57 and public health perspectives. 58 Among extensive epidemiological researches of ALS, an interesting and surprising 59 observation is that ALS patients often encounter a loss of weight or a decrease of body 60 mass index (BMI) at the early phase of diagnosis with many possible explanations [1, 61 13, 14, 15, 16, 17, 18, 19, 20]. Indeed, substan...

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Section: Methodsmentioning

confidence: 99%

Association between premorbid body mass index and amyotrophic lateral sclerosis: causal inference through genetic approaches

Zeng

2019

Preprint

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“…The primary goal of our study is to investigate whether HDL, LDL, TC or TG has any causal effect on ALS and whether such causal relationship holds in two different human populations that include both the European and East Asian populations. ALS incidence rates vary greatly across different populations and can be two to several times lower in the East Asian population than in the European population (4,7,(34)(35)(36). Therefore, examining the causal relationship between lipids and ALS in both European and East Asian populations can shade light on the similarity or difference in the genetic underpinning of ALS in different populations, facilitating coordination of ALS presentation strategies across nations.…”

Section: /34mentioning

confidence: 99%

Causal Effects of Blood Lipids on Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

Zeng

Zhou

2018

Preprint

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Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disorder that is predicted to increase across the globe by ~70% in the following decades.Understanding the disease causal mechanism underlying ALS and identifying modifiable risks factors for ALS hold the key for the development of effective preventative and treatment strategies. Here, we investigate the causal effects of four blood lipid traits that include high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG) on the risk of ALS. By leveraging instrument variables from multiple large-scale genome-wide association studies in both European and East Asian populations, we carry out one of the largest and most comprehensive Mendelian randomization analyses performed to date on the causal relationship between lipids and ALS. Among the four lipids, we found that only LDL is causally associated with ALS and that higher LDL level increases the risk of ALS in both the European and East Asian populations. Specifically, the odds ratio of ALS per one standard deviation (i.e. 39.0 mg/dL) increase of LDL is estimated to be 1.14 (95% CI 1.05 -1.24, p = 1.38E-3) in the European and population and 1.06 (95% CI 1.00 -1.12, p = 0.044) in the East Asian population. The identified causal relationship between LDL and ALS is robust with respect to the choice of statistical methods and is validated through extensive sensitivity analyses that guard against various model assumption violations. Our study provides important evidence supporting the causal role of higher LDL on increasing the risk of ALS, paving ways for the development of preventative strategies for reducing the disease burden of ALS across multiple nations. 3/34Introduction Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disorder that is characterized by progressive degeneration of upper and lower motor neurons in adults (1). Patients of ALS typically experience signs and symptoms of progressive muscle atrophy and weakness, dysphagia, dysarthria, and eventually respiratory failure. About 10% of ALS cases are familial with a Mendelian pattern of inheritance, and the remaining 90% of ALS cases are sporadic (2). The median survival time of ALS patients is only 3-5 years from the onset of symptoms with peak age of onset being 58-63 for sporadic ALS and 47-52 for familial ALS (1, 3, 4). The number of ALS cases across globe is expected to increase by ~70% in the next two and half decades, creating enormous potential social and health burden in the coming years (5).Both genetic and environmental factors contribute to the pathogenesis of ALS.Several disease genes have been identified to be associated with familial ALS and sporadic ALS. The familial ALS associated genes include SOD1, TARDBP, FUS, ANG and OPTN (1), each individually accounts for 20%, 5-10%, 5% and 1% of familiar ALS cases, respectively. The sporadic ALS associated genes include ABCG1, C9orf72, CPNE4, SARM1, MOBP, ITPR2, DPP6 and UNC13A, with all genetic varian...

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“…Two new susceptibility loci, rs6703183 covering CAMK1G and rs8141797 located in the region harboring CABIN1 and SUSD2 , were found in GWAS analysis in Han Chinese ALS (Deng et al, 2013). Afterwards, it was identified that a significant association of rs10463311 spanning GPX3-TNIP1 with ALS in the meta analysis of GWAS data from Chinese and European cohorts (Benyamin et al, 2017). Recently, NEK1 was reported a risk ALS gene based on the meta-analysis of WES data from large cohorts of Chinese and European ancestry (Gratten et al, 2017), which was consistent with the two studies from several European countries (Brenner et al, 2016; Kenna et al, 2016) and considered the first study to define a new gene with WES data in Chinese ALS.…”

Section: Genetic Characteristics Of Chinese Als Patientsmentioning

confidence: 99%

The epidemiology and genetics of Amyotrophic lateral sclerosis in China

Liu

Gao

et al. 2018

Brain Research

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with loss of motor neurons. Previous knowledge of the disease has been mainly based on studies from Caucasian ALS patients of European descent. Here we review the epidemiological characteristics of ALS among the Chinese population in order to compare the similarities and differences between Chinese ALS cases and those from other countries. We describe a potential lower incidence and prevalence of ALS, a younger age of onset and a lower proportion of familial ALS cases in the Chinese population. Additionally, we highlight potential genetic differences between Chinese and Caucasian ALS patients. Most notably, the frequency of GGGGCC repeat expansions in C9ORF72 in Chinese ALS is significantly lower than in Caucasians. Since some conclusions might not be consistent across all of the studies around China to date, we suggest that it is necessary to carry out a prospective population-based study and large-scale gene sequencing around to better define epidemiological and genetic features of Chinese ALS patients.

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Cross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis

Cited by 93 publications

References 44 publications

Association between premorbid body mass index and amyotrophic lateral sclerosis: causal inference through genetic approaches

Association between premorbid body mass index and amyotrophic lateral sclerosis: causal inference through genetic approaches

Causal Effects of Blood Lipids on Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study

The epidemiology and genetics of Amyotrophic lateral sclerosis in China

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