Architecture Of Complex Traits Research Articles

Comparison of microRNAs in adipose and muscle tissue from seven indigenous Chinese breeds and Yorkshire pigs.

Elucidation of the pig microRNAome is essential for interpreting functional elements of the genome and understanding the genetic architecture of complex traits. Here, we extracted small RNAs from skeletal muscle and adipose tissue, and we compared their expression levels between one Western breed (Yorkshire) and seven indigenous Chinese breeds. We detected the expression of 172 known porcine microRNAs (miRNAs) and 181 novel miRNAs. Differential expression analysis found 92 and 12 differentially expressed miRNAs in adipose and muscle tissue respectively. We found that different Chinese breeds shared common directional miRNA expression changes compared to Yorkshire pigs. Some miRNAs differentially expressed across multiple Chinese breeds, including ssc-miR-129-5p, ssc-miR-30 and ssc-miR-150,are involved in adipose tissue function. Functional enrichment analysis revealed that the target genes of the differentially expressed miRNAs are associated mainly with signaling pathways rather than metabolic and biosynthetic processes. The miRNA-target gene and miRNA-phenotypic traits networks identified many hub miRNAs that regulate a large number of target genes or phenotypic traits. Specifically, we found that intramuscular fat content is regulated by the greatest number of miRNAs in muscle tissue. This study provides valuable new candidate miRNAs that will aid in the improvement of meat quality and production.

Testing Pleiotropy vs. Separate QTL in Multiparental Populations

The high mapping resolution of multiparental populations, combined with technology to measure tens of thousands of phenotypes, presents a need for quantitative methods to enhance understanding of the genetic architecture of complex traits. When multiple traits map to a common genomic region, knowledge of the number of distinct loci provides important insight into the underlying mechanism and can assist planning for subsequent experiments. We extend the method of Jiang and Zeng (1995), for testing pleiotropy with a pair of traits, to the case of more than two alleles. We also incorporate polygenic random effects to account for population structure. We use a parametric bootstrap to determine statistical significance. We apply our methods to a behavioral genetics data set from Diversity Outbred mice. Our methods have been incorporated into the R package qtl2pleio.

A unified DNA sequence and non-DNA sequence mapping model of complex traits.

Increasing evidence shows that quantitative inheritance is based on both DNA sequence and non-DNA sequence variants. However, how to simultaneously detect these variants from a mapping study has been unexplored, hampering our effort to illustrate the detailed genetic architecture of complex traits. We address this issue by developing a unified model of quantitative trait locus (QTL) mapping based on an open-pollinated design composed of randomly sampling maternal plants from a natural population and their half-sib seeds. This design forms a two-level hierarchical platform for a joint linkage-linkage disequilibrium analysis of population structure. The EM algorithm was implemented to estimate and test DNA sequence-based effects and non-DNA sequence-based effects of QTLs. We applied this model to analyze genetic mapping data from the OP design of a gymnosperm coniferous species, Torreya grandis, identifying 25 significant DNA sequence and non-DNA sequence QTLs for seedling height and diameter growth in different years. Results from computer simulation show that the unified model has good statistical properties and is powerful for QTL detection. Our model enables the tests of how a complex trait is affected differently by DNA-based effects and non-DNA sequence-based transgenerational effects, thus allowing a more comprehensive picture of genetic architecture to be charted and quantified.

Funmap2: an R package for QTL mapping using longitudinal phenotypes

Quantitative trait locus (QTL) mapping has been used as a powerful tool for inferring the complexity of the genetic architecture that underlies phenotypic traits. This approach has shown its unique power to map the developmental genetic architecture of complex traits by implementing longitudinal data analysis. Here, we introduce the R package Funmap2 based on the functional mapping framework, which integrates prior biological knowledge into the statistical model. Specifically, the functional mapping framework is engineered to include longitudinal curves that describe the genetic effects and the covariance matrix of the trait of interest. Funmap2 chooses the type of longitudinal curve and covariance matrix automatically using information criteria. Funmap2 is available for download at https://github.com/wzhy2000/Funmap2.

Genotype\u2013covariate correlation and interaction disentangled by a whole-genome multivariate reaction norm model

The genomics era has brought useful tools to dissect the genetic architecture of complex traits. Here we propose a multivariate reaction norm model (MRNM) to tackle genotype–covariate (G–C) correlation and interaction problems. We apply MRNM to the UK Biobank data in analysis of body mass index using smoking quantity as a covariate, finding a highly significant G–C correlation, but only weak evidence for G–C interaction. In contrast, G–C interaction estimates are inflated in existing methods. It is also notable that there is significant heterogeneity in the estimated residual variances (i.e., variances not attributable to factors in the model) across different covariate levels, i.e., residual–covariate (R–C) interaction. We also show that the residual variances estimated by standard additive models can be inflated in the presence of G–C and/or R–C interactions. We conclude that it is essential to correctly account for both interaction and correlation in complex trait analyses.

Detection of circular RNA expression and related quantitative trait loci in the human dorsolateral prefrontal cortex

BackgroundCircular RNAs (circRNAs) are implicated in various biological processes. As a layer of the gene regulatory network, circRNA expression is also an intermediate phenotype bridging genetic variation and phenotypic changes. Thus, analyzing circRNA expression variation will shed light on molecular fundamentals of complex traits and diseases.ResultsWe systematically characterize 10,559 high-quality circRNAs in 589 human dorsolateral prefrontal cortex samples. We identify biological and technical factors contributing to expression heterogeneity associated with the expression levels of many circRNAs, including the well-known circRNA CDR1as. Combining the expression levels of circRNAs with genetic cis-acting SNPs, we detect 196,255 circRNA quantitative trait loci (circQTLs). By characterizing circQTL SNPs, we find that partial circQTL SNPs might influence circRNA formation by altering the canonical splicing site or the reverse complementary sequence match. Additionally, we find that a subset of these circQTL SNPs is highly linked to genome-wide association study signals of complex diseases, especially schizophrenia, inflammatory bowel disease, and type II diabetes mellitus.ConclusionsOur results reveal technical, biological, and genetic factors affecting circRNA expression variation among individuals, which lead to further understanding of circRNA regulation and thus of the genetic architecture of complex traits or diseases.

Trans Effects on Gene Expression Can Drive Omnigenic Inheritance

Early genome-wide association studies (GWASs) led to the surprising discovery that, for typical complex traits, most of the heritability is due to huge numbers of common variants with tiny effect sizes. Previously, we argued that new models are needed to understand these patterns. Here, we provide a formal model in which genetic contributions to complex traits are partitioned into direct effects from core genes and indirect effects from peripheral genes acting in trans. We propose that most heritability is driven by weak trans-eQTL SNPs, whose effects are mediated through peripheral genes to impact the expression of core genes. In particular, if the core genes for a trait tend to be co-regulated, then the effects of peripheral variation can be amplified such that nearly all of the genetic variance is driven by weak trans effects. Thus, our model proposes a framework for understanding key features of the architecture of complex traits.

Genomic structural equation modelling provides insights into the multivariate genetic architecture of complex traits.

Genetic correlations estimated from GWAS reveal pervasive pleiotropy across a wide variety of phenotypes. We introduce genomic structural equation modeling (Genomic SEM), a multivariate method for analyzing the joint genetic architecture of complex traits. Genomic SEM synthesizes genetic correlations and SNP-heritabilities inferred from GWAS summary statistics of individual traits from samples with varying and unknown degrees of overlap. Genomic SEM can be used to model multivariate genetic associations among phenotypes, identify variants with effects on general dimensions of cross-trait liability, calculate more predictive polygenic scores, and identify loci that cause divergence between traits. We demonstrate several applications of Genomic SEM, including a joint analysis of summary statistics from five psychiatric traits. We identify 27 independent SNPs not previously identified in the contributing univariate GWASs. Polygenic scores from Genomic SEM consistently outperform those from univariate GWAS. Genomic SEM is flexible, open ended, and allows for continuous innovation in multivariate genetic analysis.

Influence of genetic markers on the feeding behavior of yearling bulls

Background: The search for gene and marker effects on economically important traits is aimed not only to understanding the genetic architecture of complex traits but also to applying the information to breeding schemes. Objective: To analyze the effect of two temperament-related SNPs (rs109576799 located in the DRD3 gene, and rs43696138 in the HTR2A gene) on feeding performance of Mexican beef cattle. Methods: One hundred and thirty-six young beef bulls were included in a centralized feed efficiency performance test based on residual feed intake (RFI), with 20 d for adaptation and 70 d of feed efficiency testing. In addition to feeding traits, temperament was assessed at the beginning of the trial using pen score (PS) and exit velocity (EV). All animals were genotyped with two markers located in the HTR2A and DRD3 genes, and an association analysis was conducted between these genotypes and the measured traits. Results: For Brangus breed, a significant association was obtained between average daily gain (ADG; p=0.019), and the rs43696138 marker, resulting in higher gains for homozygous genotype GG (1.69 ± 0.04 kg), when compared to the heterozygous genotype GA (1.54 ± 0.04 kg). Conclusion: The previously reported association of these markers with temperament was not confirmed in the evaluated breeds; however, the rs43696138 marker showed an effect on a feeding performance trait. Further studies are needed to determine the effect of this and other markers on both RFI and temperament.

Genome-wide association study for milk production traits in a Brazilian Holstein population

Advances in the molecular area of selection have expanded knowledge of the genetic architecture of complex traits through genome-wide association studies (GWAS). Several GWAS have been performed so far, but confirming these results is not always possible due to several factors, including environmental conditions. Thus, our objective was to identify genomic regions associated with traditional milk production traits, including milk yield, somatic cell score, fat, protein and lactose percentages, and fatty acid composition in a Holstein cattle population producing under tropical conditions. For this, 75,228 phenotypic records from 5,981 cows and genotypic data of 56,256 SNP from 1,067 cows were used in a weighted single-step GWAS. A total of 46 windows of 10 SNP explaining more than 1% of the genetic variance across 10 Bos taurus autosomes (BTA) harbored well-known and novel genes. The MGST1 (BTA5), ABCG2 (BTA6), DGAT1 (BTA14), and PAEP (BTA11) genes were confirmed within some of the regions identified in our study. Potential novel genes involved in tissue damage and repair of the mammary gland (COL18A1), immune response (LTTC19), glucose homeostasis (SLC37A1), synthesis of unsaturated fatty acids (LTBP1), and sugar transport (SLC37A1 and MFSD4A) were found for milk yield, somatic cell score, fat percentage, and fatty acid composition. Our findings may assist genomic selection by using these regions to design a customized SNP array to improve milk production traits on farms with similar environmental conditions.

Methods for the Analysis and Interpretation for Rare Variants Associated with Complex Traits.

With the advent of Next Generation Sequencing (NGS) technologies, whole genome and whole exome DNA sequencing has become affordable for routine genetic studies. Coupled with improved genotyping arrays and genotype imputation methodologies, it is increasingly feasible to obtain rare genetic variant information in large datasets. Such datasets allow researchers to gain a more complete understanding of the genetic architecture of complex traits caused by rare variants. State-of-the-art statistical methods for the statistical genetics analysis of sequence-based association, including efficient algorithms for association analysis in biobank-scale datasets, gene-association tests, meta-analysis, fine mapping methods that integrate functional genomic dataset, and phenome-wide association studies (PheWAS), are reviewed here. These methods are expected to be highly useful for next generation statistical genetics analysis in the era of precision medicine. © 2019 by John Wiley & Sons, Inc.

High-resolution population structure and runs of homozygosity reveal the genetic architecture of complex traits in the Lipizzan horse

BackgroundThe sample ascertainment bias due to complex population structures remains a major challenge in genome-wide investigations of complex traits. In this study we derived the high-resolution population structure and levels of autozygosity of 377 Lipizzan horses originating from five different European stud farms utilizing the SNP genotype information of the high density 700 k Affymetrix Axiom™ Equine genotyping array. Scanning the genome for overlapping runs of homozygosity (ROH) shared by more than 50% of horses, we identified homozygous regions (ROH islands) in order to investigate the gene content of those candidate regions by gene ontology and enrichment analyses.ResultsThe high-resolution population network approach revealed well-defined substructures according to the origin of the horses (Austria, Slovakia, Croatia and Hungary). The highest mean genome coverage of ROH (SROH) was identified in the Austrian (SROH = 342.9), followed by Croatian (SROH = 214.7), Slovakian (SROH = 205.1) and Hungarian (SROH = 171.5) subpopulations. ROH island analysis revealed five common islands on ECA11 and ECA14, hereby confirming a closer genetic relationship between the Hungarian and Croatian as well as between the Austrian and Slovakian samples. Private islands were detected for the Hungarian and the Austrian Lipizzan subpopulations. All subpopulations shared a homozygous region on ECA11, nearly identical in position and length containing among other genes the homeobox-B cluster, which was also significantly (p < 0.001) highlighted by enrichment analysis. Gene ontology terms were mostly related to biological processes involved in embryonic morphogenesis and anterior/posterior specification. Around the STX17 gene (causative for greying), we identified a ROH island harbouring the genes NR4A3, STX17, ERP44 and INVS. Within further islands on ECA14, ECA16 and ECA20 we detected the genes SPRY4, NDFIP1, IMPDH2, HSP90AB1, whereas SPRY4 and HSP90AB1 are involved in melanoma metastasis and survival rate of melanoma patients in humans.ConclusionsWe demonstrated that the assessment of high-resolution population structures within one single breed supports the downstream genetic analyses (e.g. the identification of ROH islands). By means of ROH island analyses, we identified the genes SPRY4, NDFIP1, IMPDH2, HSP90AB1, which might play an important role for further studies on equine melanoma. Furthermore, our results highlighted the impact of the homeobox-A and B cluster involved in morphogenesis of Lipizzan horses.

A statistical framework for cross-tissue transcriptome-wide association analysis.

Transcriptome-wide association analysis is a powerful approach to studying the genetic architecture of complex traits. A key component of this approach is to build a model to impute gene expression levels from genotypes by using samples with matched genotypes and gene expression data in a given tissue. However, it is challenging to develop robust and accurate imputation models with a limited sample size for any single tissue. Here, we first introduce a multi-task learning method to jointly impute gene expression in 44 human tissues. Compared with single-tissue methods, our approach achieved an average of 39% improvement in imputation accuracy and generated effective imputation models for an average of 120% more genes. We describe a summary-statistic-based testing framework that combines multiple single-tissue associations into a powerful metric to quantify the overall gene-trait association. We applied our method, called UTMOST (unified test for molecular signatures), to multiple genome-wide-association results and demonstrate its advantages over single-tissue strategies.

Fast and flexible linear mixed models for genome-wide genetics.

Linear mixed effect models are powerful tools used to account for population structure in genome-wide association studies (GWASs) and estimate the genetic architecture of complex traits. However, fully-specified models are computationally demanding and common simplifications often lead to reduced power or biased inference. We describe Grid-LMM (https://github.com/deruncie/GridLMM), an extendable algorithm for repeatedly fitting complex linear models that account for multiple sources of heterogeneity, such as additive and non-additive genetic variance, spatial heterogeneity, and genotype-environment interactions. Grid-LMM can compute approximate (yet highly accurate) frequentist test statistics or Bayesian posterior summaries at a genome-wide scale in a fraction of the time compared to existing general-purpose methods. We apply Grid-LMM to two types of quantitative genetic analyses. The first is focused on accounting for spatial variability and non-additive genetic variance while scanning for QTL; and the second aims to identify gene expression traits affected by non-additive genetic variation. In both cases, modeling multiple sources of heterogeneity leads to new discoveries.

Inferring Gene Regulatory Networks from a Population of Yeast Segregants

Constructing gene regulatory networks is crucial to unraveling the genetic architecture of complex traits and to understanding the mechanisms of diseases. On the basis of gene expression and single nucleotide polymorphism data in the yeast, Saccharomyces cerevisiae, we constructed gene regulatory networks using a two-stage penalized least squares method. A large system of structural equations via optimal prediction of a set of surrogate variables was established at the first stage, followed by consistent selection of regulatory effects at the second stage. Using this approach, we identified subnetworks that were enriched in gene ontology categories, revealing directional regulatory mechanisms controlling these biological pathways. Our mapping and analysis of expression-based quantitative trait loci uncovered a known alteration of gene expression within a biological pathway that results in regulatory effects on companion pathway genes in the phosphocholine network. In addition, we identify nodes in these gene ontology-enriched subnetworks that are coordinately controlled by transcription factors driven by trans-acting expression quantitative trait loci. Altogether, the integration of documented transcription factor regulatory associations with subnetworks defined by a system of structural equations using quantitative trait loci data is an effective means to delineate the transcriptional control of biological pathways.

SA116 - A NOVEL APPROACH TO COMBINE GWAS, PGRS AND GENE-GENE INTERACTIONS IN PSYCHIATRY

Background Studies in psychiatric genetics have focused almost solely on single-loci and polygenic associations and have not included possible interactions. Nicodemus et al. (2014, JAMA Psychiatry) introduced a novel statistical model that incorporates single marker, polygenic and epistatic components to assess the association between SNPs in the ZNF804A pathway and cognitive performance in psychosis. Two-SNP interaction modelling was conducted to test for epistasis. This resulted in a regression model that contained the polygenic score and two two-SNP interaction terms, where the epistatic component explained more variation in cognition than the polygenic score. This model is still relatively simplistic in modelling the genetic architecture of complex traits; in particular, the epistatic component, as the model only allowed for pairwise interactions between SNPs. We sought to implement a more flexible specification of the epistatic component by the use of non-parametric rule sets via the algorithm C5.0. Methods As a proof-of-principle we simulated multiple phenotypes using SNPs located on chromosome 19 explaining A) 30% polygenic variation B) 30% epistatic variation using 2-SNP models not included in the polygenic set, not in LD and under weak (β=0.09), intermediate (β=0.15) and strong (β=0.24) interaction strength and C) a combination containing both a polygenic and epistatic component. Five hundred replicates were simulated per condition. We applied C5.0 in an effort to detect these epistatic interactions. C5.0 is a non-parametric algorithm to generate decision tree-based rulesets. Because of its decision tree basis C5.0 only allows for the Boolean operator OR but does allow for non-binary predictors. Each possible combination from the top node to bottom node in the tree is a so-called ruleset and can be used as a predictor in a regression model. Results We found C5.0 is highly capable of detecting both epistatic SNPs in 100% of the 500 simulations of the strong interaction, 99.2% of the intermediate interaction and 19.2% of the weak interaction models. For the intermediate and weak interactions C5.0 detected only one of the two epistatic SNPs in 0.8% and 41.2% of the replicates. C5.0 was immune to detecting polygenic additivity at the single SNP level. In the polygenic setting of 30% variation explained by an additive effect, C5.0 detected in 11.4% simulations at least one ruleset with no SNP being included more than 13 times Discussion These results show that C5.0 is able to detect epistasis even in the presence of a phenotype containing strong-single loci and polygenic components. Further work includes creating an R package that embeds these different components through a penalised regression framework to combine all three types of genetic variation (single loci, polygenic components, epistatic components) to better reflect the underlying biology, and to apply this method to cognitive performance in Major Depressive Disorder.

CoMM: A Collaborative Mixed Model That Integrates GWAS and eQTL Data Sets to Investigate the Genetic Architecture of Complex Traits.

Genome-wide association study (GWAS) analyses have identified thousands of associations between genetic variants and complex traits. However, it is still a challenge to uncover the mechanisms underlying the association. With the growing availability of transcriptome data sets, it has become possible to perform statistical analyses targeted at identifying influential genes whose expression levels correlate with the phenotype. Methods such as PrediXcan and transcriptome-wide association study (TWAS) use the transcriptome data set to fit a predictive model for gene expression, with genetic variants as covariates. The gene expression levels for the GWAS data set are then ‘imputed’ using the prediction model, and the imputed expression levels are tested for their association with the phenotype. These methods fail to account for the uncertainty in the GWAS imputation step, and we propose a collaborative mixed model (CoMM) that addresses this limitation by jointly modelling the multiple analysis steps. We illustrate CoMM’s ability to identify relevant genes in the Northern Finland Birth Cohort 1966 data set and extend the model to handle the more widely available GWAS summary statistics.

55 - LARGE META-ANALYSIS OF SCANDINAVIAN EXOME SEQUENCING STUDIES OF SCHIZOPHRENIA

Background The current data indicated that the allelic architecture of complex traits is caused by many common and rare variants. Large GWAS meta-analyses have been successfully applied in the search for common variants affecting the risk of developing psychiatric disorders, in particular schizophrenia and Major Depressive Disorder. However, these studies are designed to examine only the common variant proportion of the genomic landscape whereas high-throughput sequencing allows direct examination of both common and rare alleles. Schizophrenia is one of the most disabling mental disorders; it has a lifetime prevalence of around 1% and a heritability estimated as high as 80%. Although around one third of the heritability can be attributed to common variants, prior studies indicate that rare variants also contribute to its etiology. Methods A collaboration between iPSYCH (The Lundbeck Initiative for Integrative Psychiatric Research, Denmark) and the Broad Institute (in Cambridge, MA, USA) is conducting large scale exome sequencing of major psychiatric disorders, including schizophrenia. DNA is extracted from dried blood spots (DBS) stored at the Danish Neonatal Screening Biobank. The samples can be matched to a wide range of phenotypic information available in Danish registries. Results We present here the analysis of a large collection of schizophrenia individuals recruited in clinical centers (1,866) and from DBS samples (3,710): a total of 5,576 cases and 7,468 controls from Denmark. We follow up in a similarly sized sample from Sweden with 4,969 cases and 6,245 controls. The combined analysis represents the largest exome sequencing study in schizophrenia to date. We have found evidence showing a higher per-person rate of disruptive ultra-rare loss-of-function variants located in constrained genes among schizophrenia cases compared to controls (combined p-value 1.6e-07). Meta-analysis SKAT of rare and ultra-rare variants at gene level has been performed. Discussion The results from burden and enrichment analysis, as well as ranking of mutational load, will be discussed in the larger perspective of findings from both GWAS and other exome analyses in schizophrenia.

Crop genome-wide association study: a harvest of biological relevance.

With the advent of rapid genotyping and next-generation sequencing technologies, genome-wide association study (GWAS) has become a routine strategy for decoding genotype-phenotype associations in many species. More than 1000 such studies over the last decade have revealed substantial genotype-phenotype associations in crops and provided unparalleled opportunities to probe functional genomics. Beyond the many 'hits' obtained, this review summarizes recent efforts to increase our understanding of the genetic architecture of complex traits by focusing on non-main effects including epistasis, pleiotropy, and phenotypic plasticity. We also discuss how these achievements and the remaining gaps in our knowledge will guide future studies. Synthetic association is highlighted as leading to false causality, which is prevalent but largely underestimated. Furthermore, validation evidence is appealing for future GWAS, especially in the context of emerging genome-editing technologies.

Ethical issues in susceptibility genetic testing for late-onset neurodegenerative diseases.

Genome-wide association studies have revolutionized our understanding of the genetic architecture of complex traits and diseases over the last decade. This knowledge is enabling clinicians, researchers, and direct-to-consumer genetics companies to conduct disease susceptibility testing based on powerful methods such as polygenic risk scoring. However, these technologies raise a set of complex ethical, legal, social, and policy considerations. Here we review and discuss a series of ethical dilemmas associated with susceptibility genetic testing for the two most common late-onset neurodegenerative diseases, Alzheimer's and Parkinson's disease, including testing in asymptomatic individuals. Among others, these include informed consent, disclosure of results and unexpected findings, mandatory screening, privacy and confidentiality, and stigma and genetic discrimination. Importantly, appropriate counseling is a deciding factor for the ethical soundness of genetic testing, which poses a challenge for the regulation of these tests and the training of healthcare professionals. As genetic knowledge about these diseases continues growing and genetic testing becomes more widespread, it is increasingly important to raise awareness among researchers, medical practitioners, genetic counselors, and decision makers about the ethical, legal, and social issues associated with genetic testing for polygenic diseases.