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 in using linkage analysis in several genetic crosses for mean corpuscular volume (MCV) 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 five 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 results provide intermediate phenotypes and candidate loci for genetic studies of atherosclerosis and cancer as well as inflammatory and immune disorders in mice.     

Confirmation and fine‐mapping of clinical mastitis and somatic cell score QTL in Nordic Holstein cattle

A genome‐wide association study of 2098 progeny‐tested Nordic Holstein bulls genotyped for 36 387 SNPs on 29 autosomes was conducted to confirm and fine‐map quantitative trait loci (QTL) for mastitis traits identified earlier using linkage analysis with sparse microsatellite markers in the same population. We used linear mixed model analysis where a polygenic genetic effect was fitted as a random effect and single SNPs were successively included as fixed effects in the model. We detected 143 SNP‐by‐trait significant associations (P < 0.0001) on 20 chromosomes affecting mastitis‐related traits. Among them, 21 SNP‐by‐trait combinations exceeded the genome‐wide significant threshold. For 12 chromosomes, both the present association study and the previous linkage study detected QTL, and of these, six were in the same chromosomal locations. Strong associations of SNPs with mastitis traits were observed on bovine autosomes 6, 13, 14 and 20. Possible candidate genes for these QTL were identified. Identification of SNPs in linkage disequilibrium with QTL will enable marker‐based selection for mastitis resistance. The candidate genes identified should be further studied to detect candidate polymorphisms underlying these QTL.     

Molecular genetics of myocardial infarction

Myocardial infarction (MI) is an important clinical problem because of its large contribution to mortality. The main causal and treatable risk factors for MI include hypertension, hypercholesterolemia or dyslipidemia, diabetes mellitus, and smoking. In addition to these risk factors, recent studies have shown the importance of genetic factors and interactions between multiple genes and environmental factors. Disease prevention is an important strategy for reducing the overall burden of MI, with the identification of markers for disease risk being key both for risk prediction and for potential intervention to lower the chance of future events. Although genetic linkage analyses of families and sib-pairs as well as candidate gene and genome-wide association studies have implicated several loci and candidate genes in predisposition to coronary heart disease (CHD) or MI, the genes that contribute to genetic susceptibility to these conditions remain to be identified definitively. In this review, we summarize both candidate loci for CHD or MI identified by linkage analyses and candidate genes examined by association studies. We also review in more detail studies that have revealed the association with MI or CHD of polymorphisms in MTHFR, LPL, and APOE by the candidate gene approach and those in LTA and at chromosomal region 9p21.3 by genome-wide scans. Such studies may provide insight into the function of implicated genes as well as into the role of genetic factors in the development of CHD and MI.     

豌豆种质表型性状SSR标记关联分析

关联分析是以连锁不平衡原理为基础,鉴定某一群体内表型性状与遗传标记或候选基因间关系的遗传分析方法。本研究利用59个多态性SSR标记,对192份豌豆种质进行全基因组扫描,以分析SSR位点遗传多样性,寻找其连锁不平衡位点;采用TASSEL软件的一般线性模型,利用59个SSR标记对19个形态性状进行关联分析。结果显示SSR位点间有较高的多态性和一定程度的连锁不平衡,共检测出32个SSR标记位点与14个表形性状相关联,一些SSR标记与2个或多个形态性状相关联。     

Association of common DNA sequence variants at 33 genetic loci with blood lipids in individuals of African ancestry from Jamaica

The relevance of loci associated with blood lipids recently identified in European populations in individuals of African ancestry is unknown. We tested association between lipid traits and 36 previously described single-nucleotide polymorphisms (SNPs) in 1,466 individuals of African ancestry from Spanish Town, Jamaica. For the same allele and effect direction as observed in individuals of European ancestry, SNPs at three loci (1p13, 2p21, and 19p13) showed statistically significant association (p < 0.05) with LDL, two loci (11q12 and 20q13) showed association with HDL cholesterol, and two loci (11q12 and 2p24) showed association with triglycerides. The most significant association was between a SNP at 1p13 and LDL cholesterol (p = 4.6 × 10^?8). This SNP is in a linkage disequilibrium region containing four genes (CELSR2, PSRC1, MYBPHL, and SORT1) and was recently shown to relate to risk for myocardial infarction. Overall, the results of this study suggest that much of the genetic variation which influences blood lipids is shared across ethnic groups.     

Study of human SP-A,SP-B and SP-D loci: allele frequencies,linkage disequilibrium and heterozygosity in different races and ethnic groups

Background  

SP-A, SP-B, and SP-D are pulmonary surfactant proteins. Several linkage and association studies have been done using these genes as markers to locate pulmonary disease susceptibility genes, but few have studied the markers systematically in different ethnic groups. Here we studied eight markers in SP-A, SP-B, and SP-D genes in seven ethnic groups from three races (Caucasian, Black and Hispanic). We measured the similarity of the marker distribution among the ethnic groups in order to see whether people in different ethnic groups or races could be mixed together for linkage and association studies. To evaluate the usefulness of these markers, we estimated the informativeness of each marker loci in the seven ethnic groups by assessing their heterozygosity and PIC values. We also conducted linkage disequilibrium (LD) analysis to identify associated marker loci and to estimate the haplotype frequencies in each of the seven ethnic groups in an attempt to find valuable haplotypes so that the level of polymorphism of the "markers" could be increased.     

Natural DNA variation at candidate loci is associated with potato chip color, tuber starch content, yield and starch yield

Complex characters of plants such as starch and sugar content of seeds, fruits, tubers and roots are controlled by multiple genetic and environmental factors. Understanding their molecular basis will facilitate diagnosis and combination of superior alleles in crop improvement programs (“precision breeding”). Association genetics based on candidate genes is one approach toward this goal. Tetraploid potato varieties and breeding clones related by descent were evaluated for 2 years for chip quality before and after cold storage, tuber starch content, yield and starch yield. Chip quality is inversely correlated with tuber sugar content. A total of 36 loci on 11 potato chromosomes were evaluated for natural DNA variation in 243 individuals. These loci included microsatellites and genes coding for enzymes that function in carbohydrate metabolism or transport (candidate loci). The markers were used to analyze population structure and were tested for association with the tuber quality traits. Highly significant and robust associations of markers with 1–4 traits were identified. Most frequent were associations with chip quality and tuber starch content. Alleles increasing tuber starch content improved chip quality and vice versa. With two exceptions, the most significant and robust associations (q < 0.01) were observed with DNA variants in genes encoding enzymes that function in starch and sugar metabolism or transport. Comparing linkage and linkage disequilibrium between loci provided evidence for the existence of large haplotype blocks in the breeding materials analyzed. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Sex-specific genetic architecture of human fatness in Chinese: the SAPPHIRe Study

To dissect the genetic architecture of sexual dimorphism in obesity-related traits, we evaluated the sex–genotype interaction, sex-specific heritability and genome-wide linkages for seven measurements related to obesity. A total of 1,365 non-diabetic Chinese subjects from the family study of the Stanford Asia–Pacific Program of Hypertension and Insulin Resistance were used to search for quantitative trait loci (QTLs) responsible for the obesity-related traits. Pleiotropy and co-incidence effects from the QTLs were also examined using the bivariate linkage approach. We found that sex-specific differences in heritability and the genotype–sex interaction effects were substantially significant for most of these traits. Several QTLs with strong linkage evidence were identified after incorporating genotype by sex (G × S) interactions into the linkage mapping, including one QTL for hip circumference [maximum LOD score (MLS) = 4.22, empirical p = 0.000033] and two QTLs: for BMI on chromosome 12q with MLS 3.37 (empirical p = 0.0043) and 3.10 (empirical p = 0.0054). Sex-specific analyses demonstrated that these linkage signals all resulted from females rather than males. Most of these QTLs for obesity-related traits replicated the findings in other ethnic groups. Bivariate linkage analyses showed several obesity traits were influenced by a common set of QTLs. All regions with linkage signals were observed in one gender, but not in the whole sample, suggesting the genetic architecture of obesity-related traits does differ by gender. These findings are useful for further identification of the liability genes for these phenotypes through candidate genes or genome-wide association analysis.     

A genome-wide linkage and association scan reveals novel loci for hypertension and blood pressure traits

Hypertension is caused by the interaction of environmental and genetic factors. The condition which is very common, with about 18% of the adult Hong Kong Chinese population and over 50% of older individuals affected, is responsible for considerable morbidity and mortality. To identify genes influencing hypertension and blood pressure, we conducted a combined linkage and association study using over 500,000 single nucleotide polymorphisms (SNPs) genotyped in 328 individuals comprising 111 hypertensive probands and their siblings. Using a family-based association test, we found an association with SNPs on chromosome 5q31.1 (rs6596140; P<9 × 10(-8)) for hypertension. One candidate gene, PDC, was replicated, with rs3817586 on 1q31.1 attaining P = 2.5 × 10(-4) and 2.9 × 10(-5) in the within-family tests for DBP and MAP, respectively. We also identified regions of significant linkage for systolic and diastolic blood pressure on chromosomes 2q22 and 5p13, respectively. Further family-based association analysis of the linkage peak on chromosome 5 yielded a significant association (rs1605685, P<7 × 10(-5)) for DBP. This is the first combined linkage and association study of hypertension and its related quantitative traits with Chinese ancestry. The associations reported here account for the action of common variants whereas the discovery of linkage regions may point to novel targets for rare variant screening.     

Genetic design and statistical power of nested association mapping in maize

We investigated the genetic and statistical properties of the nested association mapping (NAM) design currently being implemented in maize (26 diverse founders and 5000 distinct immortal genotypes) to dissect the genetic basis of complex quantitative traits. The NAM design simultaneously exploits the advantages of both linkage analysis and association mapping. We demonstrated the power of NAM for high-power cost-effective genome scans through computer simulations based on empirical marker data and simulated traits with different complexities. With common-parent-specific (CPS) markers genotyped for the founders and the progenies, the inheritance of chromosome segments nested within two adjacent CPS markers was inferred through linkage. Genotyping the founders with additional high-density markers enabled the projection of genetic information, capturing linkage disequilibrium information, from founders to progenies. With 5000 genotypes, 30-79% of the simulated quantitative trait loci (QTL) were precisely identified. By integrating genetic design, natural diversity, and genomics technologies, this new complex trait dissection strategy should greatly facilitate endeavors to link molecular variation with phenotypic variation for various complex traits.     

In silico fine-mapping: narrowing disease-associated loci by intergenomics

SUMMARY: Genetic linkage and association studies define quantitative trait loci (QTLs) and susceptibility loci (SLs) that influence the phenotype of polygenic traits. A web-accessible application was created to identify intergenomic consensuses to fine map QTLs and SLs in silico and select particularly promising candidate genes for such traits. Furthermore, this approach offers an empirical evaluation of animal models for their applicability to the study of human traits. AVAILABILITY: http://qtl.pzr.uni-rostock.de/qtlmix.php CONTACT: serrano@pzr.uni-rostock.de.     

Use of the robust sib-pair method to screen for single-locus, multiple-locus, and pleiotropic effects: application to traits related to hypertension.

Robust sib-pair linkage analysis can be used as a screening tool in the search for the potential involvement of single-loci, multiple-loci, and pleiotropic effects of single loci underlying phenotypic variation. Four large families were each ascertained through one adult white male with essential hypertension. The robust sib-pair method was used to screen these families for evidence of linkage between 39 quantitative traits related to hypertension and 25 genetic marker loci. All traits were analyzed on the untransformed, square-root and log-transformed scales. Among other findings, there is a suggestion of linkage between the 6-phosphogluconate dehydrogenase locus on chromosome 1p36 and mean fifth-phase diastolic blood pressure. There may also be linkage between the following markers and traits: the adenylate kinase-1 marker and/or the Lewis blood group marker and the traits height, weight, and biacromial breadth; the glyoxylase I marker and the traits upper-arm circumference and suprailiac skinfold thickness; the ABO blood group and adenylate kinase-1 markers on chromosome 9q34 and the third component of complement marker on chromosome 19p13 and dopamine-beta-hydroxylase; and the P1 blood group and the traits weight and 1-h postload serum glucose level.     

Genetics of hypertension: From experimental animals to humans

Essential hypertension affects 20 to 30% of the population worldwide and contributes significantly to cardiovascular mortality and morbidity. Heridability of blood pressure is around 15 to 40% but there are also substantial environmental factors affecting blood pressure variability. It is assumed that blood pressure is under the control of a large number of genes each of which has only relatively mild effects. It has therefore been difficult to discover the genes that contribute to blood pressure variation using traditional approaches including candidate gene studies and linkage studies. Animal models of hypertension, particularly in the rat, have led to the discovery of quantitative trait loci harbouring one or several hypertension related genes, but translation of these findings into human essential hypertension remains challenging. Recent development of genotyping technology made large scale genome-wide association studies possible. This approach and the study of monogenic forms of hypertension has led to the discovery of novel and robust candidate genes for human essential hypertension, many of which require functional analysis in experimental models.     

Mapping of quantitative trait loci (QTLs) for oil yield using SSRs and gene-based markers in African oil palm (<Emphasis Type="Italic">Elaeis guineensis</Emphasis> Jacq.)

The identification of quantitative trait loci (QTLs) based on anchor markers, especially candidate genes that control a trait of interest, has been noted to increase the power of QTL detection. Since these markers can be scored as co-dominant data, they are also valuable for comparing and integrating the QTL linkage maps from diverse mapping populations. To estimate the position and effects of QTLs linked to oil yield traits in African oil palm, co-dominant microsatellites (SSR) and candidate gene-based sequence polymorphisms were applied to construct a linkage map for a progeny showing large differences in oil yield components. The progeny was genotyped for 97 SSR markers, 93 gene-linked markers, and 12 non-gene-linked SNP markers. From these, 190 segregating loci could be arranged into 31 linkage groups while 12 markers remained unmapped. Using the single marker linkage, interval mapping and multiple QTL methods, 16 putative QTLs on seven linkage groups affecting important oil yield related traits such as fresh fruit bunch yield (FFB), ratio of oil per fruit (OF), oil per bunch (OB), fruit per bunch (FB) and wet mesocarp per fruit (WMF) could be identified in the segregating population with estimated values for explained variance ranging from 12.4 % to 54.5 %. Markers designed from some candidate genes involved in lipid biosynthesis were found to be mapped near significant QTLs for various economic yield traits. Associations between QTLs and potential candidate genes are discussed.     

Advances in QTL mapping in pigs

Over the past 15 years advances in the porcine genetic linkage map and discovery of useful candidate genes have led to valuable gene and trait information being discovered. Early use of exotic breed crosses and now commercial breed crosses for quantitative trait loci (QTL) scans and candidate gene analyses have led to 110 publications which have identified 1,675 QTL. Additionally, these studies continue to identify genes associated with economically important traits such as growth rate, leanness, feed intake, meat quality, litter size, and disease resistance. A well developed QTL database called PigQTLdb is now as a valuable tool for summarizing and pinpointing in silico regions of interest to researchers. The commercial pig industry is actively incorporating these markers in marker-assisted selection along with traditional performance information to improve traits of economic performance. The long awaited sequencing efforts are also now beginning to provide sequence available for both comparative genomics and large scale single nucleotide polymorphism (SNP) association studies. While these advances are all positive, development of useful new trait families and measurement of new or underlying traits still limits future discoveries. A review of these developments is presented.     

Multiple genes for essential-hypertension susceptibility on chromosome 1q

Essential hypertension, defined as elevated levels of blood pressure (BP) without any obvious cause, is a major risk factor for coronary heart disease, stroke, and renal disease. BP levels and susceptibility to development of essential hypertension are partially determined by genetic factors that are poorly understood. Similar to other efforts to understand complex, non-Mendelian phenotypes, genetic dissection of hypertension-related traits employs genomewide linkage analyses of families and association studies of patient cohorts, to uncover rare and common disease alleles, respectively. Family-based mapping studies of elevated BP cover the large intermediate ground for identification of genes with common variants of significant effect. Our genomewide linkage and candidate-gene-based association studies demonstrate that a replicated linkage peak for BP regulation on human chromosome 1q, homologous to mouse and rat quantitative trait loci for BP, contains at least three genes associated with BP levels in multiple samples: ATP1B1, RGS5, and SELE. Individual variants in these three genes account for 2-5-mm Hg differences in mean systolic BP levels, and the cumulative effect reaches 8-10 mm Hg. Because the associated alleles in these genes are relatively common (frequency >5%), these three genes are important contributors to elevated BP in the population at large.     

The genetic architecture of embryonic developmental rate and genetic covariation with age at maturation in rainbow trout Oncorhynchus mykiss

The genetic architecture underlying variation in embryonic developmental rate (DR) and genetic covariation with age of maturation (MAT) was investigated in rainbow trout Oncorhynchus mykiss. Highly significant additive parental effects and more limited evidence of epistatic effects on progeny hatching time were detected in three diallel sets of families. Genome scans with an average of 142 microsatellite loci from all 29 linkage groups in two families detected significant quantitative trait loci (QTL) for developmental rate on RT-8 and RT-30 with genome-wide and chromosome-wide effects, respectively. The QTL on linkage group RT-8 explained 23·7% of the phenotypic variation and supports results from previous studies. The co-localization of QTL for both DR and MAT to several linkage groups and the observation that alleles associated with faster developmental rate were found significantly more often in early maturing rather than typical and later maturing male ancestors supports the hypothesis of genetic covariation between DR and MAT. The maturation background and schedule of additional sires, however, did not have a consistent association with their progeny hatching times, suggesting that other genetic, environmental and physiological effects contribute to variation in these life-history traits.     

The Human Obesity Gene Map: The 1997 Update

An update of the human obesity gene map incorporating published results up to October 1997 is presented. Evidence from Mendelian disorders exhibiting obesity as a clinical feature; single-gene mutation rodent models; quantitative trait loci uncovered in human genome-wide scans and in crossbreeding experiments with mouse, rat, and pig models; association and case-control studies with candidate genes; and linkage studies with genes and other markers is reviewed. All chromosomal locations of the animal loci are converted into human genome locations based on syntenic relationships between the genomes. A complete listing of all of these loci reveals that all but chromosome Y of the 24 human chromosomes are represented. Some chromosomes show at least three putative loci related to obesity on both arms (1, 2, 6, 8, 11, and 20) and several on one chromosome arm only (3p, 4q, 5q, 7q, 12q, 13q, 15q, 15p, 22q, and Xq). Studies reporting negative association and linkage results are also listed, with the exception of the unlinked markers from genome-wide scans.