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1.  Progress of genome wide association study in domestic animals 
Domestic animals are invaluable resources for study of the molecular architecture of complex traits. Although the mapping of quantitative trait loci (QTL) responsible for economically important traits in domestic animals has achieved remarkable results in recent decades, not all of the genetic variation in the complex traits has been captured because of the low density of markers used in QTL mapping studies. The genome wide association study (GWAS), which utilizes high-density single-nucleotide polymorphism (SNP), provides a new way to tackle this issue. Encouraging achievements in dissection of the genetic mechanisms of complex diseases in humans have resulted from the use of GWAS. At present, GWAS has been applied to the field of domestic animal breeding and genetics, and some advances have been made. Many genes or markers that affect economic traits of interest in domestic animals have been identified. In this review, advances in the use of GWAS in domestic animals are described.
doi:10.1186/2049-1891-3-26
PMCID: PMC3506437  PMID: 22958308
Domestic animals; Genome wide association study (GWAS); Quantitative trait loci (QTL); Single-nucleotide polymorphism (SNP)
2.  A comparison of different linkage statistics in small to moderate sized pedigrees with complex diseases 
BMC Research Notes  2012;5:411.
Background
In the last years GWA studies have successfully identified common SNPs associated with complex diseases. However, most of the variants found this way account for only a small portion of the trait variance. This fact leads researchers to focus on rare-variant mapping with large scale sequencing, which can be facilitated by using linkage information. The question arises why linkage analysis often fails to identify genes when analyzing complex diseases. Using simulations we have investigated the power of parametric and nonparametric linkage statistics (KC-LOD, NPL, LOD and MOD scores), to detect the effect of genes responsible for complex diseases using different pedigree structures.
Results
As expected, a small number of pedigrees with less than three affected individuals has low power to map disease genes with modest effect. Interestingly, the power decreases when unaffected individuals are included in the analysis, irrespective of the true mode of inheritance. Furthermore, we found that the best performing statistic depends not only on the type of pedigrees but also on the true mode of inheritance.
Conclusions
When applied in a sensible way linkage is an appropriate and robust technique to map genes for complex disease. Unlike association analysis, linkage analysis is not hampered by allelic heterogeneity. So, why does linkage analysis often fail with complex diseases? Evidently, when using an insufficient number of small pedigrees, one might miss a true genetic linkage when actually a real effect exists. Furthermore, we show that the test statistic has an important effect on the power to detect linkage as well. Therefore, a linkage analysis might fail if an inadequate test statistic is employed. We provide recommendations regarding the most favorable test statistics, in terms of power, for a given mode of inheritance and type of pedigrees under study, in order to reduce the probability to miss a true linkage.
doi:10.1186/1756-0500-5-411
PMCID: PMC3475142  PMID: 22862841
Linkage; Parametric analysis; Nonparametric analysis; NPL score; LOD score; MOD score; Complex diseases; Rare variants
3.  The power of regional heritability analysis for rare and common variant detection: simulations and application to eye biometrical traits 
Frontiers in Genetics  2013;4:232.
Genome-wide association studies (GWAS) have provided valuable insights into the genetic basis of complex traits. However, they have explained relatively little trait heritability. Recently, we proposed a new analytical approach called regional heritability mapping (RHM) that captures more of the missing genetic variation. This method is applicable both to related and unrelated populations. Here, we demonstrate the power of RHM in comparison with single-SNP GWAS and gene-based association approaches under a wide range of scenarios with variable numbers of quantitative trait loci (QTL) with common and rare causal variants in a narrow genomic region. Simulations based on real genotype data were performed to assess power to capture QTL variance, and we demonstrate that RHM has greater power to detect rare variants and/or multiple alleles in a region than other approaches. In addition, we show that RHM can capture more accurately the QTL variance, when it is caused by multiple independent effects and/or rare variants. We applied RHM to analyze three biometrical eye traits for which single-SNP GWAS have been published or performed to evaluate the effectiveness of this method in real data analysis and detected some additional loci which were not detected by other GWAS methods. RHM has the potential to explain some of missing heritability by capturing variance caused by QTL with low MAF and multiple independent QTL in a region, not captured by other GWAS methods. RHM analyses can be implemented using the software REACTA (http://www.epcc.ed.ac.uk/projects-portfolio/reacta).
doi:10.3389/fgene.2013.00232
PMCID: PMC3832942  PMID: 24312116
common and rare variants; GWAS; regional heritability mapping; multiple independent effects; missing heritability
4.  ATHENA: A TOOL FOR META-DIMENSIONAL ANALYSIS APPLIED TO GENOTYPES AND GENE EXPRESSION DATA TO PREDICT HDL CHOLESTEROL LEVELS 
Technology is driving the field of human genetics research with advances in techniques to generate high-throughput data that interrogate various levels of biological regulation. With this massive amount of data comes the important task of using powerful bioinformatics techniques to sift through the noise to find true signals that predict various human traits. A popular analytical method thus far has been the genome-wide association study (GWAS), which assesses the association of single nucleotide polymorphisms (SNPs) with the trait of interest. Unfortunately, GWAS has not been able to explain a substantial proportion of the estimated heritability for most complex traits. Due to the inherently complex nature of biology, this phenomenon could be a factor of the simplistic study design. A more powerful analysis may be a systems biology approach that integrates different types of data, or a meta-dimensional analysis. For this study we used the Analysis Tool for Heritable and Environmental Network Associations (ATHENA) to integrate high-throughput SNPs and gene expression variables (EVs) to predict high-density lipoprotein cholesterol (HDL-C) levels. We generated multivariable models that consisted of SNPs only, EVs only, and SNPs + EVs with testing r-squared values of 0.16, 0.11, and 0.18, respectively. Additionally, using just the SNPs and EVs from the best models, we generated a model with a testing r-squared of 0.32. A linear regression model with the same variables resulted in an adjusted r-squared of 0.23. With this systems biology approach, we were able to integrate different types of high-throughput data to generate meta-dimensional models that are predictive for the HDL-C in our data set. Additionally, our modeling method was able to capture more of the HDL-C variation than a linear regression model that included the same variables.
PMCID: PMC3587764  PMID: 23424143
5.  SP13 Whole-Genome Association Studies for Breast Cancer: Mapping and Directed Approaches for the Efficient Analysis of Complex Disease 
Recent technological advances in microarray technology have allowed whole-genome association studies to become possible and greatly expanded the ability to map complex genetic traits across the human genome. Current mapping array technologies offer unprecedented resolution to examine single-nucleotide polymorphisms (SNP) across the human genome. The resolution of these mapping arrays can be greatly increased by performing secondary screens using a targeted genotyping approach to further characterize SNPs discovered with the mapping arrays as well as include SNPs that are determined to be of interest in candidate genes or other genetic areas of importance.
Over the last several months, we have examined 2200 patient samples from the Shanghai Breast Cancer Study cohort using a combination of Affymetrix 500k mapping arrays and a custom 1700 SNP targeted genotyping array. Beginning with the analysis of 200 samples analyzed with the 500k mapping arrays and proceeding to 2200 samples analyzed using the custom targeted genotyping arrays, data regarding the automation of assay protocols and data analysis schemes to greatly increase the efficiency and speed of the analysis will be presented. Association statistics as well as chromosome copy number information has been produced. Data will be presented to illustrate the importance of automation, accurate sample tracking, and examination of existing data from the HapMap project in evaluating and analyzing the resulting genotyping datasets.
PMCID: PMC2291829
6.  Integrative Modeling of eQTLs and Cis-Regulatory Elements Suggests Mechanisms Underlying Cell Type Specificity of eQTLs 
PLoS Genetics  2013;9(8):e1003649.
Genetic variants in cis-regulatory elements or trans-acting regulators frequently influence the quantity and spatiotemporal distribution of gene transcription. Recent interest in expression quantitative trait locus (eQTL) mapping has paralleled the adoption of genome-wide association studies (GWAS) for the analysis of complex traits and disease in humans. Under the hypothesis that many GWAS associations tag non-coding SNPs with small effects, and that these SNPs exert phenotypic control by modifying gene expression, it has become common to interpret GWAS associations using eQTL data. To fully exploit the mechanistic interpretability of eQTL-GWAS comparisons, an improved understanding of the genetic architecture and causal mechanisms of cell type specificity of eQTLs is required. We address this need by performing an eQTL analysis in three parts: first we identified eQTLs from eleven studies on seven cell types; then we integrated eQTL data with cis-regulatory element (CRE) data from the ENCODE project; finally we built a set of classifiers to predict the cell type specificity of eQTLs. The cell type specificity of eQTLs is associated with eQTL SNP overlap with hundreds of cell type specific CRE classes, including enhancer, promoter, and repressive chromatin marks, regions of open chromatin, and many classes of DNA binding proteins. These associations provide insight into the molecular mechanisms generating the cell type specificity of eQTLs and the mode of regulation of corresponding eQTLs. Using a random forest classifier with cell specific CRE-SNP overlap as features, we demonstrate the feasibility of predicting the cell type specificity of eQTLs. We then demonstrate that CREs from a trait-associated cell type can be used to annotate GWAS associations in the absence of eQTL data for that cell type. We anticipate that such integrative, predictive modeling of cell specificity will improve our ability to understand the mechanistic basis of human complex phenotypic variation.
Author Summary
When interpreting genome-wide association studies showing that specific genetic variants are associated with disease risk, scientists look for a link between the genetic variant and a biological mechanism behind that disease. One functional mechanism is that the genetic variant may influence gene transcription via a co-localized genomic regulatory element, such as a transcription factor binding site within an open chromatin region. Often this type of regulation occurs in some cell types but not others. In this study, we look across eleven gene expression studies with seven cell types and consider how genetic transcription regulators, or eQTLs, replicate within and between cell types. We identify pervasive allelic heterogeneity, or transcriptional control of a single gene by multiple, independent eQTLs. We integrate extensive data on cell type specific regulatory elements from ENCODE to identify general methods of transcription regulation through enrichment of eQTLs within regulatory elements. We also build a classifier to predict eQTL replication across cell types. The results in this paper present a path to an integrative, predictive approach to improve our ability to understand the mechanistic basis of human phenotypic variation.
doi:10.1371/journal.pgen.1003649
PMCID: PMC3731231  PMID: 23935528
7.  Integration of biological networks and pathways with genetic association studies 
Human genetics  2012;131(10):1677-1686.
Millions of genetic variants have been assessed for their effects on the trait of interest in genome-wide association studies (GWAS). The complex traits are affected by a set of inter-related genes. However, the typical GWAS only examine the association of a single genetic variant at a time. The individual effects of a complex trait are usually small, and the simple sum of these individual effects may not reflect the holistic effect of the genetic system. High-throughput methods enable genomic studies to produce a large amount of data to expand the knowledge base of the biological systems. Biological networks and pathways are built to represent the functional or physical connectivity among genes. Integrated with GWAS data, the network- and pathway-based methods complement the approach of single genetic variant analysis, and may improve the power to identify trait-associated genes. Taking advantage of the biological knowledge, these approaches are valuable to interpret the functional role of the genetic variants, and to further understand the molecular mechanism influencing the traits. The network- and pathway-based methods have demonstrated their utilities, and will be increasingly important to address a number of challenges facing the mainstream GWAS.
doi:10.1007/s00439-012-1198-7
PMCID: PMC3432693  PMID: 22777728
8.  GUESS-ing Polygenic Associations with Multiple Phenotypes Using a GPU-Based Evolutionary Stochastic Search Algorithm 
PLoS Genetics  2013;9(8):e1003657.
Genome-wide association studies (GWAS) yielded significant advances in defining the genetic architecture of complex traits and disease. Still, a major hurdle of GWAS is narrowing down multiple genetic associations to a few causal variants for functional studies. This becomes critical in multi-phenotype GWAS where detection and interpretability of complex SNP(s)-trait(s) associations are complicated by complex Linkage Disequilibrium patterns between SNPs and correlation between traits. Here we propose a computationally efficient algorithm (GUESS) to explore complex genetic-association models and maximize genetic variant detection. We integrated our algorithm with a new Bayesian strategy for multi-phenotype analysis to identify the specific contribution of each SNP to different trait combinations and study genetic regulation of lipid metabolism in the Gutenberg Health Study (GHS). Despite the relatively small size of GHS (n = 3,175), when compared with the largest published meta-GWAS (n>100,000), GUESS recovered most of the major associations and was better at refining multi-trait associations than alternative methods. Amongst the new findings provided by GUESS, we revealed a strong association of SORT1 with TG-APOB and LIPC with TG-HDL phenotypic groups, which were overlooked in the larger meta-GWAS and not revealed by competing approaches, associations that we replicated in two independent cohorts. Moreover, we demonstrated the increased power of GUESS over alternative multi-phenotype approaches, both Bayesian and non-Bayesian, in a simulation study that mimics real-case scenarios. We showed that our parallel implementation based on Graphics Processing Units outperforms alternative multi-phenotype methods. Beyond multivariate modelling of multi-phenotypes, our Bayesian model employs a flexible hierarchical prior structure for genetic effects that adapts to any correlation structure of the predictors and increases the power to identify associated variants. This provides a powerful tool for the analysis of diverse genomic features, for instance including gene expression and exome sequencing data, where complex dependencies are present in the predictor space.
Author Summary
Nowadays, the availability of cheaper and accurate assays to quantify multiple (endo)phenotypes in large population cohorts allows multi-trait studies. However, these studies are limited by the lack of flexible models integrated with efficient computational tools for genome-wide multi SNPs-traits analyses. To overcome this problem, we propose a novel Bayesian analysis strategy and a new algorithmic implementation which exploits parallel processing architecture for fully multivariate modeling of groups of correlated phenotypes at the genome-wide scale. In addition to increased power of our algorithm over alternative Bayesian and well-established non-Bayesian multi-phenotype methods, we provide an application to a real case study of several blood lipid traits, and show how our method recovered most of the major associations and is better at refining multi-trait polygenic associations than alternative methods. We reveal and replicate in independent cohorts new associations with two phenotypic groups that were not detected by competing multivariate approaches and not noticed by a large meta-GWAS. We also discuss the applicability of the proposed method to large meta-analyses involving hundreds of thousands of individuals and to diverse genomic datasets where complex dependencies in the predictor space are present.
doi:10.1371/journal.pgen.1003657
PMCID: PMC3738451  PMID: 23950726
9.  Complex-disease networks of trait-associated single-nucleotide polymorphisms (SNPs) unveiled by information theory 
Objective
Thousands of complex-disease single-nucleotide polymorphisms (SNPs) have been discovered in genome-wide association studies (GWAS). However, these intragenic SNPs have not been collectively mined to unveil the genetic architecture between complex clinical traits. The authors hypothesize that biological annotations of host genes of trait-associated SNPs may reveal the biomolecular modularity across complex-disease traits and offer insights for drug repositioning.
Methods
Trait-to-polymorphism (SNPs) associations confirmed in GWAS were used. A novel method to quantify trait–trait similarity anchored in Gene Ontology annotations of human proteins and information theory was developed. The results were then validated with the shortest paths of physical protein interactions between biologically similar traits.
Results
A network was constructed consisting of 280 significant intertrait similarities among 177 disease traits, which covered 1438 well-validated disease-associated SNPs. Thirty-nine percent of intertrait connections were confirmed by curators, and the following additional studies demonstrated the validity of a proportion of the remainder. On a phenotypic trait level, higher Gene Ontology similarity between proteins correlated with smaller ‘shortest distance’ in protein interaction networks of complexly inherited diseases (Spearman p<2.2×10−16). Further, ‘cancer traits’ were similar to one another, as were ‘metabolic syndrome traits’ (Fisher's exact test p=0.001 and 3.5×10−7, respectively).
Conclusion
An imputed disease network by information-anchored functional similarity from GWAS trait-associated SNPs is reported. It is also demonstrated that small shortest paths of protein interactions correlate with complex-disease function. Taken together, these findings provide the framework for investigating drug targets with unbiased functional biomolecular networks rather than worn-out single-gene and subjective canonical pathway approaches.
doi:10.1136/amiajnl-2011-000482
PMCID: PMC3277620  PMID: 22278381
Complex disease; SNP; gene ontology; protein-interaction networks; information theory; translational bioinformatics; complex disease; ontology; bioinformatcis; genetics; network; prostate cancer; protein networks; pathway analysis; network modeling; knowledge representations; uncertain reasoning and decision theory; languages and computational methods
10.  Bivariate Association Analyses for the Mixture of Continuous and Binary Traits with the Use of Extended Generalized Estimating Equations 
Genetic epidemiology  2009;33(3):217-227.
Genome-wide association (GWA) study is becoming a powerful tool in deciphering genetic basis of complex human diseases/traits. Currently, the univariate analysis is the most commonly used method to identify genes associated with a certain disease/phenotype under study. A major limitation with the univariate analysis is that it may not make use of the information of multiple correlated phenotypes, which are usually measured and collected in practical studies. The multivariate analysis has proven to be a powerful approach in linkage studies of complex diseases/traits, but it has received little attention in GWA. In this study, we aim to develop a bivariate analytical method for GWAS, which can be used for a complex situation that a continuous trait and a binary trait measured are under study. Based on the modified extended generalized estimating equation (EGEE) method we proposed herein, we assessed the performance of our bivariate analyses through extensive simulations as well as real data analyses. In the study, to develop an EGEE approach for bivariate genetic analyses, we combined two different generalized linear models corresponding to phenotypic variables using a Seemingly Unrelated Regression (SUR) model. The simulation results demonstrated that our EGEE-based bivariate analytical method outperforms univariate analyses in increasing statistical power under a variety of simulation scenarios. Notably, EGEE-based bivariate analyses have consistent advantages over univariate analyses whether or not there exits a phenotypic correlation between the two traits. Our study has practical importance, as one can always use multivariate analyses as a screening tool when multiple phenotypes are available, without extra costs of statistical power and false positive rate. Analyses on empirical GWA data further affirm the advantages of our bivariate analytical method.
doi:10.1002/gepi.20372
PMCID: PMC2745071  PMID: 18924135
11.  Genome wide association studies for body conformation traits in the Chinese Holstein cattle population 
BMC Genomics  2013;14:897.
Background
Genome-wide association study (GWAS) is a powerful tool for revealing the genetic basis of quantitative traits. However, studies using GWAS for conformation traits of cattle is comparatively less. This study aims to use GWAS to find the candidates genes for body conformation traits.
Results
The Illumina BovineSNP50 BeadChip was used to identify single nucleotide polymorphisms (SNPs) that are associated with body conformation traits. A least absolute shrinkage and selection operator (LASSO) was applied to detect multiple SNPs simultaneously for 29 body conformation traits with 1,314 Chinese Holstein cattle and 52,166 SNPs. Totally, 59 genome-wide significant SNPs associated with 26 conformation traits were detected by genome-wide association analysis; five SNPs were within previously reported QTL regions (Animal Quantitative Trait Loci (QTL) database) and 11 were very close to the reported SNPs. Twenty-two SNPs were located within annotated gene regions, while the remainder were 0.6–826 kb away from known genes. Some of the genes had clear biological functions related to conformation traits. By combining information about the previously reported QTL regions and the biological functions of the genes, we identified DARC, GAS1, MTPN, HTR2A, ZNF521, PDIA6, and TMEM130 as the most promising candidate genes for capacity and body depth, chest width, foot angle, angularity, rear leg side view, teat length, and animal size traits, respectively. We also found four SNPs that affected four pairs of traits, and the genetic correlation between each pair of traits ranged from 0.35 to 0.86, suggesting that these SNPs may have a pleiotropic effect on each pair of traits.
Conclusions
A total of 59 significant SNPs associated with 26 conformation traits were identified in the Chinese Holstein population. Six promising candidate genes were suggested, and four SNPs showed genetic correlation for four pairs of traits.
doi:10.1186/1471-2164-14-897
PMCID: PMC3879203  PMID: 24341352
Dairy cattle; GWAS; Body conformation traits; SNP; Holstein; QTL
12.  Strategic Approaches to Unraveling Genetic Causes of Cardiovascular Diseases 
Circulation research  2011;108(10):1252-1269.
DNA sequence variants (DSVs) are major components of the “causal field” for virtually all-medical phenotypes, whether single-gene familial disorders or complex traits without a clear familial aggregation. The causal variants in single gene disorders are necessary and sufficient to impart large effects. In contrast, complex traits are due to a much more complicated network of contributory components that in aggregate increase the probability of disease. The conventional approach to identification of the causal variants for single gene disorders is genetic linkage. However, it does not offer sufficient resolution to map the causal genes in small size families or sporadic cases. The approach to genetic studies of complex traits entails candidate gene or Genome Wide Association Studies (GWAS). GWAS provides an unbiased survey of the effects of common genetic variants (common disease - common variant hypothesis). GWAS have led to identification of a large number of alleles for various cardiovascular diseases. However, common alleles account for a relatively small fraction of the total heritability of the traits. Accordingly, the focus has shifted toward identification of rare variants that might impart larger effect sizes (rare variant-common disease hypothesis). This shift is made feasible by recent advances in massively parallel DNA sequencing platforms, which afford the opportunity to identify virtually all common as well as rare alleles in individuals. In this review, we discuss various strategies that are used to delineate the genetic contribution to medically important cardiovascular phenotypes, emphasizing the utility of the new deep sequencing approaches.
doi:10.1161/CIRCRESAHA.110.236067
PMCID: PMC3115927  PMID: 21566222
Genetics; Next-Generation Sequencing; Complex traits; Polymorphism
13.  A Novel Approach for the Simultaneous Analysis of Common and Rare Variants in Complex Traits 
Genome-wide association studies (GWAS) have been successful in detecting common genetic variants underlying common traits and diseases. Despite the GWAS success stories, the percent trait variance explained by GWAS signals, the so called “missing heritability” has been, at best, modest. Also, the predictive power of common variants identified by GWAS has not been encouraging. Given these observations along with the fact that the effects of rare variants are often, by design, unaccounted for by GWAS and the availability of sequence data, there is a growing need for robust analytic approaches to evaluate the contribution of rare variants to common complex diseases. Here we propose a new method that enables the simultaneous analysis of the association between rare and common variants in disease etiology. We refer to this method as SCARVA (simultaneous common and rare variants analysis). SCARVA is simple to use and is efficient. We used SCARVA to analyze two independent real datasets to identify rare and common variants underlying variation in obesity among participants in the Africa America Diabetes Mellitus (AADM) study and plasma triglyceride levels in the Dallas Heart Study (DHS). We found common and rare variants associated with both traits, consistent with published results.
doi:10.4137/BBI.S8852
PMCID: PMC3273305  PMID: 22346348
association; common variant; haplotype; rare variant
14.  Molecular Genetic Studies of Complex Phenotypes 
Translational Research  2011;159(2):64-79.
The approach to molecular genetic studies of complex phenotypes has evolved considerably during the recent years. The candidate gene approach, restricted to analysis of a few single nucleotide polymorphisms (SNPs) in a modest number of cases and controls, has been supplanted by the unbiased approach of Genome-Wide Association Studies (GWAS), wherein a large number of tagger SNPs are typed in a large number of individuals. GWAS, which are designed upon the common disease- common variant hypothesis (CD-CV), have identified a large number of SNPs and loci for complex phenotypes. However, alleles identified through GWAS are typically not causative but rather in linkage disequilibrium (LD) with the true causal variants. The common alleles, which may not capture the uncommon and rare variants, account only for a fraction of heritability of the complex traits. Hence, the focus is being shifted to rare variants – common disease (RV-CD) hypothesis, surmising that rare variants exert large effect sizes on the phenotype. In conjunctional with this conceptual shift technological advances in DNA sequencing techniques have dramatically enhanced whole genome or whole exome sequencing capacity. The sequencing approach affords identification of not only the rare but also the common variants. The approach – whether used in complementation with GWAS or as a stand-alone approach - could define the genetic architecture of the complex phenotypes. Robust phenotyping and large-scale sequencing studies are essential to extract the information content of the vast number of DNA sequence variants (DSVs) in the genome. To garner meaningful clinical information and link the genotype to a phenotype, identification and characterization of a very large number of causal fields beyond the information content of DNA sequence variants would be necessary. This review provides an update on the current progress and limitations in identifying DSVs that are associated with phenotypic effects.
doi:10.1016/j.trsl.2011.08.001
PMCID: PMC3259530  PMID: 22243791
15.  Localising Loci underlying Complex Trait Variation Using Regional Genomic Relationship Mapping 
PLoS ONE  2012;7(10):e46501.
The limited proportion of complex trait variance identified in genome-wide association studies may reflect the limited power of single SNP analyses to detect either rare causative alleles or those of small effect. Motivated by studies that demonstrate that loci contributing to trait variation may contain a number of different alleles, we have developed an analytical approach termed Regional Genomic Relationship Mapping that, like linkage-based family methods, integrates variance contributed by founder gametes within a pedigree. This approach takes advantage of very distant (and unrecorded) relationships, and this greatly increases the power of the method, compared with traditional pedigree-based linkage analyses. By integrating variance contributed by founder gametes in the population, our approach provides an estimate of the Regional Heritability attributable to a small genomic region (e.g. 100 SNP window covering ca. 1 Mb of DNA in a 300000 SNP GWAS) and has the power to detect regions containing multiple alleles that individually contribute too little variance to be detectable by GWAS as well as regions with single common GWAS-detectable SNPs. We use genome-wide SNP array data to obtain both a genome-wide relationship matrix and regional relationship (“identity by state" or IBS) matrices for sequential regions across the genome. We then estimate a heritability for each region sequentially in our genome-wide scan. We demonstrate by simulation and with real data that, when compared to traditional (“individual SNP") GWAS, our method uncovers new loci that explain additional trait variation. We analysed data from three Southern European populations and from Orkney for exemplar traits – serum uric acid concentration and height. We show that regional heritability estimates are correlated with results from genome-wide association analysis but can capture more of the genetic variance segregating in the population and identify additional trait loci.
doi:10.1371/journal.pone.0046501
PMCID: PMC3471913  PMID: 23077511
16.  Genome-wide Association Mapping of Blood Cell Traits in Mice 
Genetic variations in blood cell parameters can impact clinical traits. We report here the mapping of blood cell traits in a panel of 100 inbred strains of mice of the Hybrid Mouse Diversity Panel (HMDP) using genome-wide association (GWA). We replicated a locus previously identified using linkage analysis in several genetic crosses for mean corpuscular volume 1 and a number of other red blood cell traits on distal chromosome 7. Our peak for SNP association to MCV occurred in a linkage disequilibrium (LD) block spanning from 109.38 to 111.75 Mb that includes Hbb-b1, the likely causal gene. Altogether, we identified 5 loci controlling red blood cell traits (on chromosomes 1, 7, 11, 12, and 16), and four of these correspond to loci for red blood cell traits reported in a recent human GWA study. For white blood cells, including granulocytes, monocytes, and lymphocytes, a total of six significant loci were identified on chromosomes 1, 6, 8, 11, 12 and 15. An average of ten candidate genes were found at each locus and those were prioritized by examining functional variants in the HMDP such as missense and expression variants. These new results provide intermediate phenotypes and candidate loci for genetic studies of atherosclerosis and cancer as well as inflammatory and immune disorders in mice.
doi:10.1007/s00335-013-9448-0
PMCID: PMC3933005  PMID: 23417284
blood cell traits; genetics; association; linkage; red cell; white cell; mice
17.  A consensus linkage map of the grass carp (Ctenopharyngodon idella) based on microsatellites and SNPs 
BMC Genomics  2010;11:135.
Background
Grass carp (Ctenopharyngodon idella) belongs to the family Cyprinidae which includes more than 2000 fish species. It is one of the most important freshwater food fish species in world aquaculture. A linkage map is an essential framework for mapping traits of interest and is often the first step towards understanding genome evolution. The aim of this study is to construct a first generation genetic map of grass carp using microsatellites and SNPs to generate a new resource for mapping QTL for economically important traits and to conduct a comparative mapping analysis to shed new insights into the evolution of fish genomes.
Results
We constructed a first generation linkage map of grass carp with a mapping panel containing two F1 families including 192 progenies. Sixteen SNPs in genes and 263 microsatellite markers were mapped to twenty-four linkage groups (LGs). The number of LGs was corresponding to the haploid chromosome number of grass carp. The sex-specific map was 1149.4 and 888.8 cM long in females and males respectively whereas the sex-averaged map spanned 1176.1 cM. The average resolution of the map was 4.2 cM/locus. BLAST searches of sequences of mapped markers of grass carp against the whole genome sequence of zebrafish revealed substantial macrosynteny relationship and extensive colinearity of markers between grass carp and zebrafish.
Conclusions
The linkage map of grass carp presented here is the first linkage map of a food fish species based on co-dominant markers in the family Cyprinidae. This map provides a valuable resource for mapping phenotypic variations and serves as a reference to approach comparative genomics and understand the evolution of fish genomes and could be complementary to grass carp genome sequencing project.
doi:10.1186/1471-2164-11-135
PMCID: PMC2838847  PMID: 20181260
18.  Association Mapping of Insecticide Resistance in Wild Anopheles gambiae Populations: Major Variants Identified in a Low-Linkage Disequilbrium Genome 
PLoS ONE  2010;5(10):e13140.
Background
Association studies are a promising way to uncover the genetic basis of complex traits in wild populations. Data on population stratification, linkage disequilibrium and distribution of variant effect-sizes for different trait-types are required to predict study success but are lacking for most taxa. We quantified and investigated the impacts of these key variables in a large-scale association study of a strongly selected trait of medical importance: pyrethroid resistance in the African malaria vector Anopheles gambiae.
Methodology/Principal Findings
We genotyped ≈1500 resistance-phenotyped wild mosquitoes from Ghana and Cameroon using a 1536-SNP array enriched for candidate insecticide resistance gene SNPs. Three factors greatly impacted study power. (1) Population stratification, which was attributable to co-occurrence of molecular forms (M and S), and cryptic within-form stratification necessitating both a partitioned analysis and genomic control. (2) All SNPs of substantial effect (odds ratio, OR>2) were rare (minor allele frequency, MAF<0.05). (3) Linkage disequilibrium (LD) was very low throughout most of the genome. Nevertheless, locally high LD, consistent with a recent selective sweep, and uniformly high ORs in each subsample facilitated significant direct and indirect detection of the known insecticide target site mutation kdr L1014F (OR≈6; P<10−6), but with resistance level modified by local haplotypic background.
Conclusion
Primarily as a result of very low LD in wild A. Gambiae, LD-based association mapping is challenging, but is feasible at least for major effect variants, especially where LD is enhanced by selective sweeps. Such variants will be of greatest importance for predictive diagnostic screening.
doi:10.1371/journal.pone.0013140
PMCID: PMC2956759  PMID: 20976111
19.  From genetical genomics to systems genetics: potential applications in quantitative genomics and animal breeding 
Mammalian Genome  2006;17:548-564.
This article reviews methods of integration of transcriptomics (and equally proteomics and metabolomics), genetics, and genomics in the form of systems genetics into existing genome analyses and their potential use in animal breeding and quantitative genomic modeling of complex traits. Genetical genomics or the expression quantitative trait loci (eQTL) mapping method and key findings in this research are reviewed. Various procedures and potential uses of eQTL mapping, global linkage clustering, and systems genetics are illustrated using actual analysis on recombinant inbred lines of mice with data on gene expression (for diabetes- and obesity-related genes), pathway, and single nucleotide polymorphism (SNP) linkage maps. Experimental and bioinformatics difficulties and possible solutions are discussed. The main uses of this systems genetics approach in quantitative genomics were shown to be in refinement of the identified QTL, candidate gene and SNP discovery, understanding gene-environment and gene-gene interactions, detection of candidate regulator genes/eQTL, discriminating multiple QTL/eQTL, and detection of pleiotropic QTL/eQTL, in addition to its use in reconstructing regulatory networks. The potential uses in animal breeding are direct selection on heritable gene expression measures, termed “expression assisted selection,” and genetical genomic selection of both QTL and eQTL based on breeding values of the respective genes, termed “expression-assisted evaluation.”
doi:10.1007/s00335-005-0169-x
PMCID: PMC3906707  PMID: 16783637
20.  Application of Association Mapping to Understanding the Genetic Diversity of Plant Germplasm Resources 
Compared to the conventional linkage mapping, linkage disequilibrium (LD)-mapping, using the nonrandom associations of loci in haplotypes, is a powerful high-resolution mapping tool for complex quantitative traits. The recent advances in the development of unbiased association mapping approaches for plant population with their successful applications in dissecting a number of simple to complex traits in many crop species demonstrate a flourish of the approach as a “powerful gene tagging” tool for crops in the plant genomics era of 21st century. The goal of this review is to provide nonexpert readers of crop breeding community with (1) the basic concept, merits, and simple description of existing methodologies for an association mapping with the recent improvements for plant populations, and (2) the details of some of pioneer and recent studies on association mapping in various crop species to demonstrate the feasibility, success, problems, and future perspectives of the efforts in plants. This should be helpful for interested readers of international plant research community as a guideline for the basic understanding, choosing the appropriate methods, and its application.
doi:10.1155/2008/574927
PMCID: PMC2423417  PMID: 18551188
21.  A GENOME-WIDE LINKAGE AND ASSOCIATION SCAN REVEALS NOVEL LOCI FOR AUTISM 
Nature  2009;461(7265):802-808.
Summary
Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success 1. Genome-wide association studies (GWAS) using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits (http://www.genome.gov/26525384). Consequently, we initiated a linkage and association mapping study using half a million genome-wide SNPs in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed a SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 × 10−7). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening while the discovery of a single novel association demonstrates the action of common variants.
doi:10.1038/nature08490
PMCID: PMC2772655  PMID: 19812673
22.  Quantitative Genetics in the Genomics Era 
Current Genomics  2012;13(3):196-206.
The genetic analysis of quantitative or complex traits has been based mainly on statistical quantities such as genetic variances and heritability. These analyses continue to be developed, for example in studies of natural populations. Genomic methods are having an impact on progress and prospects. Actual relationships of individuals can be estimated enabling novel quantitative analyses. Increasing precision of linkage mapping is feasible with dense marker panels and designed stocks allowing multiple generations of recombination, and large SNP panels enable the use of genome wide association analysis utilising historical recombination. Whilst such analyses are identifying many loci for disease genes and traits such as height, typically each individually contributes a small amount of the variation. Only by fitting all SNPs without regard to significance can a high proportion be accounted for, so a classical polygenic model with near infinitesimally small effects remains a useful one. Theory indicates that a high proportion of variants will have low minor allele frequency, making detection difficult. Genomic selection, based on simultaneously fitting very dense markers and incorporating these with phenotypic data in breeding value prediction is revolutionising breeding programmes in agriculture and has a major potential role in human disease prediction.
doi:10.2174/138920212800543110
PMCID: PMC3382274  PMID: 23115521
Complex traits; evolution; heritability; genetic variance; genome wide association; QTL; selection.
23.  ATOM: a powerful gene-based association test by combining optimally weighted markers 
Bioinformatics  2008;25(4):497-503.
Background: Large-scale candidate-gene and genome-wide association studies genotype multiple SNPs within or surrounding a gene, including both tag and functional SNPs. The immense amount of data generated in these studies poses new challenges to analysis. One particularly challenging yet important question is how to best use all genetic information to test whether a gene or a region is associated with the trait of interest.
Methods: Here we propose a powerful gene-based Association Test by combining Optimally Weighted Markers (ATOM) within a genomic region. Due to variation in linkage disequilibrium, different markers often associate with the trait of interest at different levels. To appropriately apportion their contributions, we assign a weight to each marker that is proportional to the amount of information it captures about the trait locus. We analytically derive the optimal weights for both quantitative and binary traits, and describe a procedure for estimating the weights from a reference database such as the HapMap. Compared with existing approaches, our method has several distinct advantages, including (i) the ability to borrow information from an external database to increase power, (ii) the theoretical derivation of optimal marker weights and (iii) the scalability to simultaneous analysis of all SNPs in candidate genes and pathways.
Results: Through extensive simulations and analysis of the FTO gene in our ongoing genome-wide association study on childhood obesity, we demonstrate that ATOM increases the power to detect genetic association as compared with several commonly used multi-marker association tests.
Contact: mingyao@mail.med.upenn.edu; chun.li@vanderbilt.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btn641
PMCID: PMC2642636  PMID: 19074959
24.  An Integration of Genome-Wide Association Study and Gene Expression Profiling to Prioritize the Discovery of Novel Susceptibility Loci for Osteoporosis-Related Traits 
PLoS Genetics  2010;6(6):e1000977.
Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS) have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW). A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6×10−8), 2q11.2 (TBC1D8), and 18q11.2 (OSBPL1A), and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6×10−13; SOX6, p = 6.4×10−10) associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant to the skeletal system in cellular or whole animal models to prioritize candidate genes for further functional validation.
Author Summary
BMD and hip geometry are two major predictors of osteoporotic fractures, the most severe consequence of osteoporosis in elderly persons. We performed sex-specific genome-wide association studies (GWAS) for BMD at the lumbar spine and femor neck skeletal sites as well as hip geometric indices (NSA, NL, and NW) in the Framingham Osteoporosis Study and then replicated the top findings in two independent studies. Three novel loci were significant: in women, including chromosome 1p13.2 (RAP1A) for NW; in men, 2q11.2 (TBC1D8) for NSA and 18q11.2 (OSBPL1A) for NW. We confirmed a previously reported region on 8q24.12 (TNFRSF11B/OPG) for lumbar spine BMD in women. In addition, we integrated GWAS signals with eQTL in several tissues and publicly available expression signature profiling in cellular and whole-animal models, and prioritized 16 candidate genes/loci based on their potential involvement in skeletal metabolism. Among three prioritized loci (GPR177, SOX6, and CASR genes) associated with BMD in women, GPR177 and SOX6 have been successfully replicated later in a large-scale meta-analysis, but none of the non-prioritized candidates (associated with BMD) did. Our results support the concept of using expression profiling to support the candidacy of suggestive GWAS signals that may contain important genes of interest.
doi:10.1371/journal.pgen.1000977
PMCID: PMC2883588  PMID: 20548944
25.  Genome-Wide Association Study of Schizophrenia in Japanese Population 
PLoS ONE  2011;6(6):e20468.
Schizophrenia is a devastating neuropsychiatric disorder with genetically complex traits. Genetic variants should explain a considerable portion of the risk for schizophrenia, and genome-wide association study (GWAS) is a potentially powerful tool for identifying the risk variants that underlie the disease. Here, we report the results of a three-stage analysis of three independent cohorts consisting of a total of 2,535 samples from Japanese and Chinese populations for searching schizophrenia susceptibility genes using a GWAS approach. Firstly, we examined 115,770 single nucleotide polymorphisms (SNPs) in 120 patient-parents trio samples from Japanese schizophrenia pedigrees. In stage II, we evaluated 1,632 SNPs (1,159 SNPs of p<0.01 and 473 SNPs of p<0.05 that located in previously reported linkage regions). The second sample consisted of 1,012 case-control samples of Japanese origin. The most significant p value was obtained for the SNP in the ELAVL2 [(embryonic lethal, abnormal vision, Drosophila)-like 2] gene located on 9p21.3 (p = 0.00087). In stage III, we scrutinized the ELAVL2 gene by genotyping gene-centric tagSNPs in the third sample set of 293 family samples (1,163 individuals) of Chinese descent and the SNP in the gene showed a nominal association with schizophrenia in Chinese population (p = 0.026). The current data in Asian population would be helpful for deciphering ethnic diversity of schizophrenia etiology.
doi:10.1371/journal.pone.0020468
PMCID: PMC3108953  PMID: 21674006

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