Autosomal genome-wide linkage analysis to identify loci for gallbladder wall thickness in Mexican Americans

The significance of gallbladder wall thickness (GBWT) in regard to gallbladder disease (GBD) is not completely understood. Thickening of the gallbladder wall has been observed in patients with acute calculous and acalculous cholecystitis and chronic cholecystitis. However, various pathologic processes, such as gallbladder cancer and nonbiliary disorders such as liver cirrhosis and viral hepatitis, could also cause thickening of the gallbladder wall. To date, there is no report available on the genetic factors influencing GBWT. Therefore we sought to estimate the heritability (h2) of GBWT and to perform a genome-wide search to identify the susceptibility genes for GBWT, using data from the San Antonio Family Diabetes/Gallbladder Study (SAFDGS), a family study of Mexican Americans. GBWT was measured by ultrasound. After adjusting for the significant effects of age, sex, GBD (i.e., asymptomatic gallstones), metabolic syndrome, and duration of type 2 diabetes (T2DM), GBWT was found to be under significant and appreciable additive genetic influences (h2 +/- SE = 0.38 +/- 0.09, P < 0.0001). The strongest evidence for linkage occurred between markers D11S912 and D11S968 on chromosome 11q24-q25 (LOD = 2.7), where we have already shown suggestive evidence for linkage of GBD (LOD = 2.7) in a subset of our SAFDGS data. Potential evidence for linkage occurred at markers D1S1728 (1p31.1; LOD = 1.4) and D16S748 (16p13.1; LOD = 1.4), respectively. In conclusion, our study provides suggestive evidence for linkage of GBWT on chromosome 11q in Mexican Americans, and future tasks of mapping susceptibility gene(s) for GBD and its related traits, such as GBWT, in this chromosomal region can be fruitful.     

A meta-analysis of two genome-wide association studies to identify novel loci for maximum number of alcoholic drinks

Maximum number of alcoholic drinks consumed in a 24-h period (maxdrinks) is a heritable (>50 %) trait and is strongly correlated with vulnerability to excessive alcohol consumption and subsequent alcohol dependence (AD). Several genome-wide association studies (GWAS) have studied alcohol dependence, but few have concentrated on excessive alcohol consumption. We performed two GWAS using maxdrinks as an excessive alcohol consumption phenotype: one in 118 extended families (N = 2,322) selected from the Collaborative Study on the Genetics of Alcoholism (COGA), and the other in a case–control sample (N = 2,593) derived from the Study of Addiction: Genes and Environment (SAGE). The strongest association in the COGA families was detected with rs9523562 (p = 2.1 × 10^?6) located in an intergenic region on chromosome 13q31.1; the strongest association in the SAGE dataset was with rs67666182 (p = 7.1 × 10^?7), located in an intergenic region on chromosome 8. We also performed a meta-analysis with these two GWAS and demonstrated evidence of association in both datasets for the LMO1 (p = 7.2 × 10^?7) and PLCL1 genes (p = 4.1 × 10^?6) with maxdrinks. A variant in AUTS2 and variants in INADL, C15orf32 and HIP1 that were associated with measures of alcohol consumption in a meta-analysis of GWAS studies and a GWAS of alcohol consumption factor score also showed nominal association in the current meta-analysis. The present study has identified several loci that warrant further examination in independent samples. Among the top SNPs in each of the dataset (p ≤ 10^?4) far more showed the same direction of effect in the other dataset than would be expected by chance (p = 2 × 10^?3, 3 × 10^?6), suggesting that there are true signals among these top SNPs, even though no SNP reached genome-wide levels of significance.     

Bayesian model selection for genome-wide epistatic quantitative trait loci analysis

The problem of identifying complex epistatic quantitative trait loci (QTL) across the entire genome continues to be a formidable challenge for geneticists. The complexity of genome-wide epistatic analysis results mainly from the number of QTL being unknown and the number of possible epistatic effects being huge. In this article, we use a composite model space approach to develop a Bayesian model selection framework for identifying epistatic QTL for complex traits in experimental crosses from two inbred lines. By placing a liberal constraint on the upper bound of the number of detectable QTL we restrict attention to models of fixed dimension, greatly simplifying calculations. Indicators specify which main and epistatic effects of putative QTL are included. We detail how to use prior knowledge to bound the number of detectable QTL and to specify prior distributions for indicators of genetic effects. We develop a computationally efficient Markov chain Monte Carlo (MCMC) algorithm using the Gibbs sampler and Metropolis-Hastings algorithm to explore the posterior distribution. We illustrate the proposed method by detecting new epistatic QTL for obesity in a backcross of CAST/Ei mice onto M16i.     

Detection of susceptibility loci by genome-wide linkage analysis

The objective of this study is to evaluate the efficacy of a model-free linkage statistics for finding evidence of linkage using two different maps and to illustrate how the comparison of results from several populations might provide insight into the underlying genetic etiology of the disease of interest. The results obtained in terms of detection of the risk loci and threshold for declaring linkage and power are very similar for a dense SNP map and a sparser microsatellite map. The populations differed in terms of family ascertainment and diagnosis criteria, leading to different power to detect the individual underlying disease loci. Our results for the individual replicates are consistent with the disease model used in the simulation.     

A genome-wide approach to identify genetic loci with a signature of natural selection in the Irish population

Background  

In this study we present a single population test (Ewens-Waterson) applied in a genomic context to investigate the presence of recent positive selection in the Irish population. The Irish population is an interesting focus for the investigation of recent selection since several lines of evidence suggest that it may have a relatively undisturbed genetic heritage.     

Detection of loci for allergic asthma using SMXA recombinant inbred strains of mice

Asthma is regarded as a multifactorial inflammatory disorder arising as a result of inappropriate immune responses in genetically susceptible individuals to common environmental antigens. However, the precise molecular basis is unknown. To identify genes for susceptibility to three asthma-related traits, airway hyperresponsiveness (AHR), eosinophil infiltration, and allergen-specific serum IgE levels, we conducted a genetic analysis using SMXA recombinant inbred (RI) strains of mice. Quantitative trait locus analysis detected a significant locus for AHR on chromosome 17. For eosinophil infiltration, significant loci were detected on chromosomes 9 and 16. Although we could not detect any significant loci for allergen-specific serum IgE, analysis of consomic strains showed that chromosomes 17 and 19 carried genes that affected this trait. We detected genetic susceptibility loci that separately regulated the three asthma-related phenotypes. Our results suggested that different genetic mechanisms regulate these asthma-related phenotypes. Genetic analyses using murine RI and consomic strains enhance understanding of the molecular mechanisms of asthma in human.     

A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci

Crohn''s disease (CD) is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD–susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2–4 times more prevalent among individuals of Ashkenazi Jewish (AJ) descent compared to non-Jewish Europeans (NJ). To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS) by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10⁻⁶). Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10⁻⁸; combined odds ratio OR = 1.48), 2p15 (rs6545946, p = 7×10⁻⁹; OR = 1.16), 8q21.11 (rs12677663, p = 2×10⁻⁸; OR = 1.15), 10q26.3 (rs10734105, p = 3×10⁻⁸; OR = 1.27), and 11q12.1 (rs11229030, p = 8×10⁻⁹; OR = 1.15), implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.     

A genome-wide scan for loci linked to forearm bone mineral density

Osteoporosis is a chronic disorder characterized by low bone mass and fragility fractures. It affects more than 25 million men and women in the United States alone. Although several candidate genes, such as the vitamin-D-receptor gene or the estrogen-receptor gene, have been suggested in the pathogenesis of osteoporosis, the genetic dissection of this disorder remains a daunting task. To search systematically for chromosomal regions containing genes that regulate bone mineral density (BMD), we scanned the entire autosomal genome by using 367 polymorphic markers among 218 individuals (153 sibpairs) from 96 nuclear families collected from three townships of Anqing, China. In these 96 families, DNA samples from both parents were available for 82 (85.4%) families. By using age- and gender-adjusted forearm BMD measurements, a peak on chromosome 2 near D2S2141, D2S1400, and D2S405, a region previously linked to spinal BMD, showed evidence of linkage to both proximal and distal forearm BMD (multipoint LOD=2.15 and 2.14 for proximal and distal forearm BMD, respectively). One region on chromosome 13 (multipoint LOD=1.67) in the proximity of D13S788 and D13S800 showed evidence of linkage to distal forearm BMD only. Possible candidate genes included CALM2 (calmodulin 2) at 2p21.3-p21.1, a putative STK (serine/threonine kinase) at 2p23–24, POMC (pro-opiomelanocortin) at 2p23.3, and COL4A1 and COL4A2 (collagen IV alpha-1 and alpha-2 subunits) at 13q34. Because of the limited sample size, the suggestive evidence of linkage of this study should be considered as tentative and needs to be replicated in other larger populations. Received: 19 November 1998 / Accepted: 22 January 1999     

Combining genome-wide association mapping and transcriptional networks to identify novel genes controlling glucosinolates in Arabidopsis thaliana

Background

Genome-wide association (GWA) is gaining popularity as a means to study the architecture of complex quantitative traits, partially due to the improvement of high-throughput low-cost genotyping and phenotyping technologies. Glucosinolate (GSL) secondary metabolites within Arabidopsis spp. can serve as a model system to understand the genomic architecture of adaptive quantitative traits. GSL are key anti-herbivory defenses that impart adaptive advantages within field trials. While little is known about how variation in the external or internal environment of an organism may influence the efficiency of GWA, GSL variation is known to be highly dependent upon the external stresses and developmental processes of the plant lending it to be an excellent model for studying conditional GWA.

Methodology/Principal Findings

To understand how development and environment can influence GWA, we conducted a study using 96 Arabidopsis thaliana accessions, >40 GSL phenotypes across three conditions (one developmental comparison and one environmental comparison) and ∼230,000 SNPs. Developmental stage had dramatic effects on the outcome of GWA, with each stage identifying different loci associated with GSL traits. Further, while the molecular bases of numerous quantitative trait loci (QTL) controlling GSL traits have been identified, there is currently no estimate of how many additional genes may control natural variation in these traits. We developed a novel co-expression network approach to prioritize the thousands of GWA candidates and successfully validated a large number of these genes as influencing GSL accumulation within A. thaliana using single gene isogenic lines.

Conclusions/Significance

Together, these results suggest that complex traits imparting environmentally contingent adaptive advantages are likely influenced by up to thousands of loci that are sensitive to fluctuations in the environment or developmental state of the organism. Additionally, while GWA is highly conditional upon genetics, the use of additional genomic information can rapidly identify causal loci en masse.     

Application of genome-wide expression analysis to identify molecular markers useful in monitoring industrial fermentations

Genome-wide expression analysis of an industrial strain of Saccharomyces cerevisiae identified the YOR387c and YGL258w homologues as highly inducible in zinc-depleted conditions. Induction was specific for zinc deficiency and was dependent on Zap1p. The results indicate that these sequences may be valuable molecular markers for detecting zinc deficiency in industrial fermentations.     

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.     

Applying novel genome-wide linkage strategies to search for loci influencing type 2 diabetes and adult height in American Samoa

Type 2 diabetes mellitus (T2DM) is a common complex phenotype that by the year 2010 is predicted to affect 221 million people globally. In the present study we performed a genome-wide linkage scan using the allele-sharing statistic Sall implemented in Allegro and a novel two-dimensional genome-wide strategy implemented in Merloc that searches for pairwise interaction between genetic markers located on different chromosomes linked to T2DM. In addition, we used a robust score statistic from the newly developed QTL-ALL software to search for linkage to variation in adult height. The strategies were applied to a study sample consisting of 238 sib-pairs affected with T2DM from American Samoa. We did not detect any genome-wide significant susceptibility loci for T2DM. However, our two-dimensional linkage investigation detected several loci pairs of interest, including 11q22 and 21q21, 9q21 and 11q22, 1p22-p21 and 4p15, and 4p15 and 15q11-q14, with a two-loci maximum LOD score (MLS) greater than 2.00. Most detected individual loci have previously been identified as susceptibility loci for diabetes-related traits. Our two-dimensional linkage results may facilitate the selection of potential candidate genes and molecular pathways for further diabetes studies because these results, besides providing candidate loci, also demonstrate that polygenic effects may play an important role in T2DM. Linkage was detected (p value of 0.005) for variation in adult height on chromosome 9q31, which was reported previously in other populations. Our finding suggests that the 9q31 region may be a strong quantitative trait locus for adult height, which is likely to be of importance across populations.     

Replication of genome-wide association studies on asthma and allergic diseases in Korean adult population

Allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis are heterogeneous diseases characterized by multiple symptoms and phenotypes. Recent advancements in genetic study enabled us to identify disease associated genetic factors. Numerous genome-wide association studies (GWAS) have revealed multiple associated loci for allergic diseases. However, the majority of previous studies have been conducted in populations of European ancestry. Moreover, the associations of single nucleotide polymorphisms (SNPs) with allergic diseases have not been studied amongst the large-scale general Korean population. Herein, we performed the replication study to validate the previous variants, known to be associated with allergic diseases, in the Korean population. In this study, we categorized three allergic related phenotypes, one allergy and two asthma related phenotypes, based on self-reports of physician diagnosis and their symptoms from 8,842 samples. As a result, we found nominally significant associations of 6 SNPs with at least one allergic related phenotype in the Korean population.     

Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease

Although the causes of Parkinson's disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD-rs6812193 near SCARB2 (p = 7.6 × 10(-10), OR = 0.84) and rs11868035 near SREBF1/RAI1 (p = 5.6 × 10(-8), OR = 0.85)-both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%-7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered.     

Sex-specific regulation of mitochondrial DNA levels: genome-wide linkage analysis to identify quantitative trait Loci

Altered mitochondrial DNA (mtDNA) levels have been associated with common diseases in humans. We investigated the genetic mechanism that controls mtDNA levels using genome-wide linkage analyses in families from the Genetic Analysis of Idiopathic Thrombophilia Project (GAIT). We measure mtDNA levels by quantitative real-time PCR in 386 subjects from 21 extended Spanish families. A variance component linkage method using 485 microsatellites was conducted to evaluate linkage and to detect quantitative trait loci (QTLs) involved in the control of mtDNA levels. The heritalibility of mtDNA levels was 0.33 (p = 1.82e-05). We identified a QTL on Chromosome 2 (LOD = 2.21) using all of the subjects, independently on their sex. When females and males were analysed separately, three QTLs were identified. Females showed the same QTL on Chromosome 2 (LOD = 3.09), indicating that the QTL identified in the analysis using all of the subjects was a strong female QTL, and another one on Chromosome 3 (LOD = 2.67), whereas in males a QTL was identified on Chromosome 1 (LOD = 2.81). These QTLs were fine-mapped to find associations with mtDNA levels. The most significant SNP association was for the rs10888838 on Chromosome 1 in males. This SNP mapped to the gene MRPL37, involved in mitochondrial protein translation. The rs2140855 on Chromosome 2 showed association in the analysis using all of the subjects. It was near the gene CMPK2, which encodes a mitochondrial enzyme of the salvage pathway of deoxyribonucleotide synthesis. Our results provide evidence of a sex-specific genetic mechanism for the control of mtDNA levels and provide a framework to identify new genes that influence mtDNA levels.     

Early‐life environment,developmental immunotoxicology,and the risk of pediatric allergic disease including asthma

Incidence of childhood allergic disease including asthma (AD‐A) has risen since the mid‐20th century with much of the increase linked to changes in environment affecting the immune system. Childhood allergy is an early life disease where predisposing environmental exposures, sensitization, and onset of symptoms all occur before adulthood. Predisposition toward allergic disease (AD) is among the constellation of adverse outcomes following developmental immunotoxicity (DIT; problematic exposure of the developing immune system to xenobiotics and physical environmental factors). Because novel immune maturation events occur in early life, and the pregnancy state itself imposes certain restrictions on immune functional development, the period from mid‐gestation until 2 years after birth is one of particular concern relative to DIT and AD‐A. Several prenatal‐perinatal risk factors have been identified as contributing to a DIT‐mediated immune dysfunction and increased risk of AD. These include maternal smoking, environmental tobacco smoke, diesel exhaust and traffic‐related particles, heavy metals, antibiotics, environmental estrogens and other endocrine disruptors, and alcohol. Diet and microbial exposure also significantly influence immune maturation and risk of allergy. This review considers (1) the critical developmental windows of vulnerability for the immune system that appear to be targets for risk of AD, (2) a model in which the immune system of the DIT‐affected infant exhibits immune dysfunction skewed toward AD, and (3) the lack of allergy‐relevant safety testing of drugs and chemicals that could identify DIT hazards and minimize problematic exposure of pregnant women and children. Birth Defects Res (Part B) 2008. © 2008 Wiley‐Liss, Inc.