Causal inference for heritable phenotypic risk factors using heterogeneous genetic instruments

Over a decade of genome-wide association studies (GWAS) have led to the finding of extreme polygenicity of complex traits. The phenomenon that “all genes affect every complex trait” complicates Mendelian Randomization (MR) studies, where natural genetic variations are used as instruments to infer the causal effect of heritable risk factors. We reexamine the assumptions of existing MR methods and show how they need to be clarified to allow for pervasive horizontal pleiotropy and heterogeneous effect sizes. We propose a comprehensive framework GRAPPLE to analyze the causal effect of target risk factors with heterogeneous genetic instruments and identify possible pleiotropic patterns from data. By using GWAS summary statistics, GRAPPLE can efficiently use both strong and weak genetic instruments, detect the existence of multiple pleiotropic pathways, determine the causal direction and perform multivariable MR to adjust for confounding risk factors. With GRAPPLE, we analyze the effect of blood lipids, body mass index, and systolic blood pressure on 25 disease outcomes, gaining new information on their causal relationships and the potential pleiotropic pathways.

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Causal Inference for Heritable Phenotypic Risk Factors Using Heterogeneous Genetic Instruments

10.1101/2020.05.06.077982 ◽

2020 ◽

Author(s):

Jingshu Wang ◽

Qingyuan Zhao ◽

Jack Bowden ◽

Gilbran Hemani ◽

George Davey Smith ◽

...

Keyword(s):

Risk Factors ◽

Complex Traits ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genetic Associations ◽

Genome Wide ◽

Genetic Instruments

Over a decade of genome-wide association studies have led to the finding that significant genetic associations tend to spread across the genome for complex traits. The extreme polygenicity where "all genes affect every complex trait" complicates Mendelian Randomization studies, where natural genetic variations are used as instruments to infer the causal effect of heritable risk factors. We reexamine the assumptions of existing Mendelian Randomization methods and show how they need to be clarified to allow for pervasive horizontal pleiotropy and heterogeneous effect sizes. We propose a comprehensive framework GRAPPLE (Genome-wide mR Analysis under Pervasive PLEiotropy) to analyze the causal effect of target risk factors with heterogeneous genetic instruments and identify possible pleiotropic patterns from data. By using summary statistics from genome-wide association studies, GRAPPLE can efficiently use both strong and weak genetic instruments, detect the existence of multiple pleiotropic pathways, adjust for confounding risk factors, and determine the causal direction. With GRAPPLE, we analyze the effect of blood lipids, body mass index, and systolic blood pressure on 25 disease outcomes, gaining new information on their causal relationships and the potential pleiotropic pathways.

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Joint Genome-Wide Association Study Identifies Twenty-One Novel Loci for Age at Menarche and Highlights Its Causal Association with Other Complex Diseases

10.21203/rs.3.rs-955340/v1 ◽

2021 ◽

Author(s):

Gui-Juan Feng ◽

Qian Xu ◽

Jing-Jing Ni ◽

Shan-Shan Yang ◽

Bai-Xue Han ◽

...

Keyword(s):

Association Study ◽

Complex Traits ◽

Causal Effect ◽

Association Studies ◽

Genetic Correlations ◽

Genome Wide Association ◽

Age At Menarche ◽

Luteinizing Hormone Level ◽

Genome Wide Association Studies ◽

Genome Wide

Abstract Age at menarche (AAM) is a sign of puberty of females. It is a heritable trait associated with various adult diseases. However, the genetic mechanism that determines AAM and links it to disease risk is poorly understood. Aiming to uncover the genetic basis for AAM, we conducted a joint association study in up to 438,089 participants from 3 genome-wide association studies of European and East Asian ancestries. Twenty-one novel genomic loci were identified at the genome-wide significance level. Besides, we observed significant genetic correlations between AAM and 67 complex traits, and the highest genetic correlation was observed between AAM and body mass index (rg=-0.19, P=6.11×10−31). Latent causal variable analyses demonstrate that there is a genetically causal effect of AAM on high blood pressure (GCP=0.47, P=0.02), forced vital capacity (GCP=0.63, P=0.02), age at first live birth (GCP=0.51, P=0.03), impedance of right arm (GCP=0.41, P<1×10-7) and right leg fat percentage (GCP=-0.10, P=0.02), etc. Enrichment analysis identified 5 enriched tissues and 51 enriched gene sets. Four of the five enriched tissues were related to the nervous system, including the hypothalamus middle, hypothalamo hypophyseal system, neurosecretory systems and hypothalamus. The fifth tissue was the retina in the sensory organ. The most significant gene set was the ‘decreased circulating luteinizing hormone level’ (P=2.45×10-6). Our findings may provide useful insights that elucidate the mechanisms determining AAM and the genetic interplay between AAM and some traits of women.

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True causal effect size heterogeneity is not required to explain trans-ethnic differences in GWAS signals

10.1101/085092 ◽

2016 ◽

Cited By ~ 3

Author(s):

Daniela Zanetti ◽

Michael E. Weale

Keyword(s):

Ethnic Differences ◽

Effect Size ◽

Complex Traits ◽

Causal Effect ◽

Association Studies ◽

African Ancestry ◽

Causal Variant ◽

Genome Wide Association Studies ◽

Population Differences ◽

Relative Risks

AbstractThrough genome-wide association studies (GWASs), researchers have identified hundreds of genetic variants associated with particular complex traits. Previous studies have compared the pattern of association signals across different populations in real data, and these have detected differences in the strength and sometimes even the direction of GWAS signals. These differences could be due to a combination of (1) lack of power (insufficient sample sizes); (2) minor allele frequency (MAF) differences (again affecting power); (3) linkage disequilibrium (LD) differences (affecting power to ‘tag’ the causal variant); and (4) true differences in causal variant effect sizes (defined by relative risks).In the present work, we sought to assess whether the first three of these reasons are sufficient on their own to explain the observed incidence of trans-ethnic differences in replications of GWAS signals, or whether the fourth reason is also required. We simulated case-control data of European, Asian and African ancestry, drawing on observed MAF and LD patterns seen in the 1000-Genomes reference dataset and assuming the true causal relative risks were the same in all three populations.We found that a combination of Euro-centric SNP selection and between-population differences in LD, accentuated by the lower SNP density typical of older GWAS panels, was sufficient to explain the rate of trans-ethnic differences previously reported, without the need to assume between-population differences in true causal SNP effect size. This suggests a cross-population consistency that has implications for our understanding of the interplay between genetics and environment in the aetiology of complex human diseases.

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Bayesian weighted Mendelian randomization for causal inference based on summary statistics

Bioinformatics ◽

10.1093/bioinformatics/btz749 ◽

2019 ◽

Author(s):

Jia Zhao ◽

Jingsi Ming ◽

Xianghong Hu ◽

Gang Chen ◽

Jin Liu ◽

...

Keyword(s):

Causal Inference ◽

Complex Traits ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Supplementary Information ◽

Genome Wide Association Studies ◽

Simulation Studies ◽

Genome Wide ◽

Complex Human Traits

Abstract Motivation The results from Genome-Wide Association Studies (GWAS) on thousands of phenotypes provide an unprecedented opportunity to infer the causal effect of one phenotype (exposure) on another (outcome). Mendelian randomization (MR), an instrumental variable (IV) method, has been introduced for causal inference using GWAS data. Due to the polygenic architecture of complex traits/diseases and the ubiquity of pleiotropy, however, MR has many unique challenges compared to conventional IV methods. Results We propose a Bayesian weighted Mendelian randomization (BWMR) for causal inference to address these challenges. In our BWMR model, the uncertainty of weak effects owing to polygenicity has been taken into account and the violation of IV assumption due to pleiotropy has been addressed through outlier detection by Bayesian weighting. To make the causal inference based on BWMR computationally stable and efficient, we developed a variational expectation-maximization (VEM) algorithm. Moreover, we have also derived an exact closed-form formula to correct the posterior covariance which is often underestimated in variational inference. Through comprehensive simulation studies, we evaluated the performance of BWMR, demonstrating the advantage of BWMR over its competitors. Then we applied BWMR to make causal inference between 130 metabolites and 93 complex human traits, uncovering novel causal relationship between exposure and outcome traits. Availability and implementation The BWMR software is available at https://github.com/jiazhao97/BWMR. Supplementary information Supplementary data are available at Bioinformatics online.

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An iterative approach to detect pleiotropy and perform Mendelian Randomization analysis using GWAS summary statistics

Bioinformatics ◽

10.1093/bioinformatics/btaa985 ◽

2020 ◽

Author(s):

Xiaofeng Zhu ◽

Xiaoyin Li ◽

Rong Xu ◽

Tao Wang

Keyword(s):

Complex Traits ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Real Data ◽

Supplementary Information ◽

Genome Wide Association Studies ◽

Summary Statistics ◽

Causal Relationships ◽

Multiple Traits

Abstract Motivation The overall association evidence of a genetic variant with multiple traits can be evaluated by cross-phenotype association analysis using summary statistics from genome-wide association studies. Further dissecting the association pathways from a variant to multiple traits is important to understand the biological causal relationships among complex traits. Results Here, we introduce a flexible and computationally efficient Iterative Mendelian Randomization and Pleiotropy (IMRP) approach to simultaneously search for horizontal pleiotropic variants and estimate causal effect. Extensive simulations and real data applications suggest that IMRP has similar or better performance than existing Mendelian Randomization methods for both causal effect estimation and pleiotropic variant detection. The developed pleiotropy test is further extended to detect colocalization for multiple variants at a locus. IMRP will greatly facilitate our understanding of causal relationships underlying complex traits, in particular, when a large number of genetic instrumental variables are used for evaluating multiple traits. Availability and implementation The software IMRP is available at https://github.com/XiaofengZhuCase/IMRP. The simulation codes can be downloaded at http://hal.case.edu/∼xxz10/zhu-web/ under the link: MR Simulations software. Supplementary information Supplementary data are available at Bioinformatics online.

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Quantifying genetic heterogeneity between continental populations for human height and body mass index

Scientific Reports ◽

10.1038/s41598-021-84739-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jing Guo ◽

Andrew Bakshi ◽

Ying Wang ◽

Longda Jiang ◽

Loic Yengo ◽

...

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Complex Traits ◽

Association Studies ◽

Significant Snps ◽

Complex Trait ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Population Difference ◽

Genome Wide

AbstractGenome-wide association studies (GWAS) in samples of European ancestry have identified thousands of genetic variants associated with complex traits in humans. However, it remains largely unclear whether these associations can be used in non-European populations. Here, we seek to quantify the proportion of genetic variation for a complex trait shared between continental populations. We estimated the between-population correlation of genetic effects at all SNPs ($$r_{g}$$ r g ) or genome-wide significant SNPs ($$r_{{g\left( {GWS} \right)}}$$ r g GWS ) for height and body mass index (BMI) in samples of European (EUR; $$n = 49,839$$ n = 49 , 839 ) and African (AFR; $$n = 17,426$$ n = 17 , 426 ) ancestry. The $$\hat{r}_{g}$$ r ^ g between EUR and AFR was 0.75 ($${\text{s}}.{\text{e}}. = 0.035$$ s . e . = 0.035 ) for height and 0.68 ($${\text{s}}.{\text{e}}. = 0.062$$ s . e . = 0.062 ) for BMI, and the corresponding $$\hat{r}_{{g\left( {GWS} \right)}}$$ r ^ g GWS was 0.82 ($${\text{s}}.{\text{e}}. = 0.030$$ s . e . = 0.030 ) for height and 0.87 ($${\text{s}}.{\text{e}}. = 0.064$$ s . e . = 0.064 ) for BMI, suggesting that a large proportion of GWAS findings discovered in Europeans are likely applicable to non-Europeans for height and BMI. There was no evidence that $$\hat{r}_{g}$$ r ^ g differs in SNP groups with different levels of between-population difference in allele frequency or linkage disequilibrium, which, however, can be due to the lack of power.

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Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus

Nature Communications ◽

10.1038/s41467-021-27198-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Adrienne Tin ◽

Pascal Schlosser ◽

Pamela R. Matias-Garcia ◽

Chris H. L. Thio ◽

Roby Joehanes ◽

...

Keyword(s):

Dna Methylation ◽

Complex Traits ◽

Cardiometabolic Risk ◽

Association Studies ◽

Meta Analysis ◽

Elevated Serum ◽

Complex Trait ◽

Serum Urate ◽

Genome Wide Association Studies ◽

Genome Wide

AbstractElevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E–7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

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The role of gene expression on human sexual dimorphism: too early to call

10.1101/2020.04.15.042986 ◽

2020 ◽

Cited By ~ 1

Author(s):

Eleonora Porcu ◽

Annique Claringbould ◽

Kaido Lepik ◽

Tom G. Richardson ◽

Federico A. Santoni ◽

...

Keyword(s):

Sexual Dimorphism ◽

Complex Traits ◽

Causal Effect ◽

Association Studies ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome ◽

Specific Trait ◽

Trait Associations

AbstractThe genetic underpinning of sexual dimorphism is very poorly understood. The prevalence of many diseases differs between men and women, which could be in part caused by sex-specific genetic effects. Nevertheless, only a few published genome-wide association studies (GWAS) were performed separately in each sex. The reported enrichment of expression quantitative trait loci (eQTLs) among GWAS–associated SNPs suggests a potential role of sex-specific eQTLs in the sex-specific genetic mechanism underlying complex traits.To explore this scenario, we performed a genome-wide analysis of sex-specific whole blood RNA-seq eQTLs from 3,447 individuals. Among 9 million SNP-gene pairs showing sex-combined associations, we found 18 genes with significant sex-specific cis-eQTLs (FDR 5%). Our phenome-wide association study of the 18 top sex-specific eQTLs on >700 traits unraveled that these eQTLs do not systematically translate into detectable sex-specific trait-associations. Power analyses using real eQTL- and causal effect sizes showed that millions of samples would be necessary to observe sex-specific trait associations that are fully driven by sex-specific cis-eQTLs. Compensatory effects may further hamper their detection. In line with this observation, we confirmed that the sex-specific trait-associations detected so far are not driven by sex-specific cis-eQTLs.

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Testing and controlling for horizontal pleiotropy with the probabilistic Mendelian randomization in transcriptome-wide association studies

10.1101/691014 ◽

2019 ◽

Cited By ~ 3

Author(s):

Zhongshang Yuan ◽

Huanhuan Zhu ◽

Ping Zeng ◽

Sheng Yang ◽

Shiquan Sun ◽

...

Keyword(s):

Complex Traits ◽

Molecular Mechanisms ◽

Mendelian Randomization ◽

Causal Effect ◽

Association Studies ◽

Pleiotropic Effects ◽

Type I ◽

Genome Wide Association Studies ◽

Wide Spread ◽

Disease Etiology

AbstractIntegrating association results from both genome-wide association studies (GWASs) and expression quantitative trait locus (eQTL) mapping studies has the potential to shed light on the molecular mechanisms underlying disease etiology. Several statistical methods have been recently developed to integrate GWASs with eQTL studies in the form of transcriptome-wide association studies (TWASs). These existing methods can all be viewed as a form of two sample Mendelian randomization (MR) analysis, which has been widely applied in various GWASs for inferring the causal relationship among complex traits. Unfortunately, most existing TWAS and MR methods make an unrealistic modeling assumption and assume that instrumental variables do not exhibit horizontal pleiotropic effects. However, horizontal pleiotropic effects have been recently discovered to be wide spread across complex traits, and, as we will show here, are also wide spread across gene expression traits. Therefore, not allowing for horizontal pleiotropic effects can be overly restrictive, and, as we will be show here, can lead to a substantial inflation of test statistics and subsequently false discoveries in TWAS applications. Here, we present a probabilistic MR method, which we refer to as PMR-Egger, for testing and controlling for horizontal pleiotropic effects in TWAS applications. PMR-Egger relies on an MR likelihood framework that unifies many existing TWAS and MR methods, accommodates multiple correlated instruments, tests the causal effect of gene on trait in the presence of horizontal pleiotropy, and, with a newly developed parameter expansion version of the expectation maximization algorithm, is scalable to hundreds of thousands of individuals. With extensive simulations, we show that PMR-Egger provides calibrated type I error control for causal effect testing in the presence of horizontal pleiotropic effects, is reasonably robust for various types of horizontal pleiotropic effect mis-specifications, is more powerful than existing MR approaches, and, as a by-product, can directly test for horizontal pleiotropy. We illustrate the benefits of PMR-Egger in applications to 39 diseases and complex traits obtained from three GWASs including the UK Biobank. In these applications, we show how PMR-Egger can lead to new biological discoveries through integrative analysis.

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Quantifying genetic heterogeneity between continental populations for human height and body mass index

10.1101/839373 ◽

2019 ◽

Cited By ~ 2

Author(s):

Jing Guo ◽

Andrew Bakshi ◽

Ying Wang ◽

Longda Jiang ◽

Loic Yengo ◽

...

Keyword(s):

Body Mass Index ◽

Body Mass ◽

Complex Traits ◽

Association Studies ◽

Significant Snps ◽

Complex Trait ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Population Difference ◽

Genome Wide

AbstractGenome-wide association studies (GWAS) in samples of European ancestry have identified thousands of genetic variants associated with complex traits in humans. However, it remains largely unclear whether these associations can be used in non-European populations. Here, we seek to quantify the proportion of genetic variation for a complex trait shared between continental populations. We estimated the between-population correlation of genetic effects at all SNPs (rg) or genome-wide significant SNPs (rg(GWS)) for height and body mass index (BMI) in samples of European (EUR; n = 49,839) and African (AFR; n = 17,426) ancestry. The between EUR and AFR was 0.75 (s. e. = 0.035) for height and 0.68 (s. e. = 0.062) for BMI, and the corresponding was 0.82 (s. e. = 0.030) for height and 0.87 (s. e. = 0.064) for BMI, suggesting that a large proportion of GWAS findings discovered in Europeans are likely applicable to non-Europeans for height and BMI. There was no evidence that differs in SNP groups with different levels of between-population difference in allele frequency or linkage disequilibrium, which, however, can be due to the lack of power.

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