An hour in the morning is worth two in the evening: association of morning component of morningness–eveningness with single nucleotide polymorphisms in circadian clock genes

Sub-constructs of morning–evening preference might be differentially related to polymorphisms in circadian clock genes. We previously reported significant association between a single nucleotide polymorphism in PER3 (rs2640909) and Morning but not Evening Lateness scale of the Sleep–Wake Pattern Assessment Questionnaire. To further explore such a scale-specific relationship, seven single nucleotide polymorphisms in five circadian clock genes were studied using exploratory and confirmatory samples (in total, n = 698). The association of rs2640909 with Morning Lateness scale was not replicated in the confirmatory sample but remained significant in the merged sample. Moreover, we found and confirmed an association of this scale with rs1159814 in RORα. The results provided further evidence for differential relationship of polymorphisms in circadian clock genes with morning and evening components of morning–evening preference. We also suggested possibility to take into account the pattern of geographic variation in allele frequency for prioritization of circadian clock polymorphisms in candidate gene studies.     

Molecular genetics of cognitive deficit in schizophrenia

Cognitive deficit is a key feature of schizophrenia. Genetic factors are thought to contribute to cognitive disturbances in schizophrenia patients. However the role of specific-genes in the development of cognitive deficit remains unclear. The article aims at reviewing the current studies devoted to association between gene polymorphisms and cognitive dysfunctions in schizophrenic patients. Main attention is drawn to the association between the Val158Met polymorphism of the COMT gene and cognitive traits that has been consistently replicated and has a biological and neuropsychological support. The association studies on the genes for dopamine and serotonin receptors, brain-derived neurotrophic factor, dysbindin, DISC1, D-amino acid oxidase and D-amino acid oxidase activator are reviewed as well.     

A study of the possible association between adenosine A2A receptor gene polymorphisms and attention‐deficit hyperactivity disorder traits

The adenosine A_2A receptor (ADORA2A) is linked to the dopamine neurotransmitter system and is also implicated in the regulation of alertness, suggesting a potential association with attention‐deficit hyperactivity disorder (ADHD) traits. Furthermore, animal studies suggest that the ADORA2A may influence ADHD‐like behavior. For that reason, the ADORA2A gene emerges as a promising candidate for studying the etiology of ADHD traits. The aim of this study was to examine the relationship between ADORA2A gene polymorphisms and ADHD traits in a large population‐based sample. This study was based on the Child and Adolescent Twin Study in Sweden (CATSS), and included 1747 twins. Attention‐deficit hyperactivity disorder traits were assessed through parental reports, and samples of DNA were collected. Associations between six single nucleotide polymorphisms (SNPs) and ADHD traits were examined, and results suggested a nominal association between ADHD traits and three of these SNPs: rs3761422, rs5751876 and rs35320474. For one of the SNPs, rs35320474, results remained significant after correction for multiple comparisons. These results indicate the possibility that the ADORA2A gene may be involved in ADHD traits. However, more studies replicating the present results are warranted before this association can be confirmed .     

FTO gene variants are associated with growth and carcass traits in cattle

An important aim in animal breeding is the improvement of growth and meat quality traits. Previous studies have demonstrated that genetic variants in the fat mass and obesity associated (FTO) gene have a relatively large effect on human obesity as well as on body composition in rodents and, more recently, in livestock. Here, we examined the effects of the FTO gene variants on growth and carcass traits in the Slovenian population of Simmental (SS) and Brown (SB) cattle. To validate and identify new polymorphisms, we used sequencing, PCR‐RFLP analysis and TaqMan assays in the SS breed and FTO gene variants data from the Illumina BovineSNP50 v1 array for the SB breed. Sequencing of the eight samples of progeny‐tested SS sires detected 108 single nucleotide polymorphisms (SNPs) in the bovine FTO gene. Statistical analyses between growth and carcass traits and 34 FTO polymorphisms revealed significant association of FTO variants with lean meat percentage in both breeds. Additionally, FTO SNPs analyzed in SS cattle were associated with fat percentage, bone weight and live weight at slaughter. The FTO gene can thus be regarded as a candidate gene for the marker‐assisted selection programs in our and possibly other populations of cattle. Future studies in cattle might reveal novel roles for the FTO gene in shaping carcass traits in livestock species as well as body composition control in other mammals.     

Remarkable genetic diversity detected at river buffalo prolactin receptor (PRLR) gene and association studies with milk fatty acid composition

Prolactin is an anterior pituitary peptide hormone involved in many different endocrine activities and is essential for reproductive performance. This action is mediated by its receptor, the prolactin receptor, encoded by the PRLR gene. In this study, we sequenced and characterized the Mediterranean river buffalo PRLR gene (from exon 3 to 10), and we found remarkable genetic diversity. In particular, we found 24 intronic polymorphisms and 13 exonic SNPs, seven of which were non‐synonymous. Furthermore, the polymorphisms identified in the 3′‐UTR were investigated to establish their possible influence on microRNA binding sites. Considering all the amino acid changes and the observed allelic combinations, it is possible to deduce at least six different translations of the buffalo prolactin receptor and, consequently, the presence at the PRLR gene of at least six alleles. Furthermore, we identified a deletion of a CACTACC heptamer between nucleotides 1102 and 1103 of exon 10 (3′‐UTR), and we developed an allele‐specific PCR to identify the carriers of this genetic marker. Finally, the SNP g.11188A>G, detected in exon 10 and responsible for the amino acid replacement p.His328Arg, was genotyped in 308 Italian Mediterranean river buffaloes, and an association study with milk fat traits was carried out. The statistical analysis showed a tendency that approached significance for the AA genotype with higher contents of odd branched‐chain fatty acids. Thus, our results suggest that the PRLR gene is a good candidate for gene association studies with qualitative traits related to buffalo milk production.     

The role of gene polymorphisms in the pathogenesis of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Irreversible airflow limitation, both progressive and associated with an inflammatory response of the lungs to noxious particles or gases, is a hallmark of the disease. Cigarette smoking is the most important environmental risk factor for COPD, nevertheless, only approximately 20–30% of smokers develop symptomatic disease. Epidemiological studies, case-control studies in relatives of patients with COPD, and twin studies suggest that COPD is a genetically complex disease with environmental factors and many involved genes interacting together. Two major strategies have been employed to identify the genes and the polymorphisms that likely contribute to the development of complex diseases: association studies and linkage analyses. Biologically plausible pathogenetic mechanisms are prerequisites to focus the search for genes of known function in association studies. Protease-antiprotease imbalance, generation of oxidative stress, and chronic inflammation are recognized as the principal mechanisms leading to irreversible airflow obstruction and parenchymal destruction in the lung. Therefore, genes which have been implicated in the pathogenesis of COPD are involved in antiproteolysis, antioxidant barrier and metabolism of xenobiotic substances, inflammatory response to cigarette smoke, airway hyperresponsiveness, and pulmonary vascular remodelling. Significant associations with COPD-related phenotypes have been reported for polymorphisms in genes coding for matrix metalloproteinases, microsomal epoxide hydrolase, glutathione-S-transferases, heme oxygenase, tumor necrosis factor, interleukines 1, 8, and 13, vitamin D-binding protein and β-2-adrenergic receptor (ADRB2), whereas adequately powered replication studies failed to confirm most of the previously observed associations. Genome-wide linkage analyses provide us with a novel tool to identify the general locations of COPD susceptibility genes, and should be followed by association analyses of positional candidate genes from COPD pathophysiology, positional candidate genes selected from gene expression studies, or dense single nucleotide polymorphism panels across regions of linkage. Haplotype analyses of genes with multiple polymorphic sites in linkage disequilibrium, such as the ADRB2 gene, provide another promising field that has yet to be explored in patients with COPD. In the present article we review the current knowledge about gene polymorphisms that have been recently linked to the risk of developing COPD and/or may account for variations in the disease course.     

Candidate gene polymorphisms for behavioural adaptations during urbanization in blackbirds

Successful urban colonization by formerly rural species represents an ideal situation in which to study adaptation to novel environments. We address this issue using candidate genes for behavioural traits that are expected to play a role in such colonization events. We identified and genotyped 16 polymorphisms in candidate genes for circadian rhythms, harm avoidance and migratory and exploratory behaviour in 12 paired urban and rural populations of the blackbird Turdus merula across the Western Palaearctic. An exonic microsatellite in the SERT gene, a candidate gene for harm avoidance behaviour, exhibited a highly significant association with habitat type in an analysis conducted across all populations. Genetic divergence at this locus was consistent in 10 of the 12 population pairs; this contrasts with previously reported stochastic genetic divergence between these populations at random markers. Our results indicate that behavioural traits related to harm avoidance and associated with the SERT polymorphism experience selection pressures during most blackbird urbanization events. These events thus appear to be influenced by homogeneous adaptive processes in addition to previously reported demographic founder events.     

Association of GSTM1 and GSTT1 Polymorphisms with Chronic Obstructive Pulmonary Disease in a Tunisian Population

GSTM1 and GSTT1 polymorphisms have been proposed in relationship with chronic obstructive pulmonary disease (COPD). We investigated the association between these polymorphisms and COPD (as well as its subtypes emphysema and chronic bronchitis) in 234 COPD patients and 182 healthy controls in the Tunisian population. Genotyping was performed using multiplex PCR. GSTM1-null genotype frequency was significantly higher in COPD patients than in controls (P = 0.02); however, multivariate analysis of cofounding variables showed no independent association with this genotype (P = 0.073). In contrast, the association of the GSTM1-null genotype with emphysema was significant, even after adjustment for risk factors (P = 0.011). There were no significant differences in GSTT1 genotypes between patients and controls. The GSTM1 null allele is likely not an independent risk factor for COPD but is related to emphysema, whereas the GSTT1 gene is not associated with the disease.     

Molecular genetic studies of cognitive deficit in schizophrenia

Cognitive deficit is a key feature of schizophrenia. Genetic factors are thought to contribute to cognitive disturbances in schizophrenic patients. However, the role of specific genes in the development of cognitive deficit remains elusive. The review considers the current studies on the association between gene polymorphisms and cognitive dysfunction in schizophrenics. Main attention is drawn to the consistently reproducible association between the COMT polymorphism Val158Met and cognitive traits, which has a biological and neuropsychological support. The association studies with the genes for the dopamine and serotonin receptors, brain-derived neurotrophic factor, dysbindin, DISC1, D-amino acid oxidase, and D-amino acid oxidase activator are reviewed as well.     

徐淮白山羊DGAT2基因内含子3多态性与生长性状关联分析

目的：探讨DGAT2基因内含子3的遗传多态性及其与山羊生长性状的关联。方法：采用PCR-SSCP、DNA序列分析及生物信息学技术研究徐淮白山羊DGAT2基因内含子3的多态性及其与山羊生长性状的关联情况。结果：徐淮白山羊DGAT2基因内含子3存在A、B2个等位基因,其基因频率依次为0.9550、0.0450,并且处于Hardy-Weinberg平衡状态;徐淮白山羊DGAT2基因不同基因型对徐淮白山羊体高有显著影响（P〈0.05）,而对其他体尺指标在统计学上无显著影响（P〉0.05）。结论：DGAT2基因内含子3的遗传多态性与徐淮白山羊生长性状存在相关。     

A candidate gene association study for nine economically important traits in Italian Holstein cattle

We genotyped 58 single nucleotide polymorphisms (SNPs) in 25 candidate genes in about 800 Italian Holstein sires. Fifty‐six (minor allele frequency >0.02) were used to evaluate their association with single traits: milk yield (MY), milk fat yield (FY), milk protein yield (PY), milk fat percentage (FP), milk protein percentage (PP), milk somatic cell count (MSCC); and complex indexes: longevity, fertility and productivity–functionality type (PFT), using deregressed proofs, after adjustment for familial relatedness. Thirty‐two SNPs were significantly associated (proportion of false positives <0.05) with different traits: 16 with MSCC, 15 with PY, 14 with MY, 12 with PFT, eight with longevity, eight with FY, eight with PP, five with FP and two with fertility. In particular, a SNP in the promoter region of the PRLR gene was associated with eight of nine traits. DGAT1 polymorphisms were highly associated with FP and FY. Casein gene markers were associated with several traits, confirming the role of the casein gene cluster in affecting milk yield, milk quality and health traits. Other SNPs in genes located on chromosome 6 were associated with PY, PP, PFT, MY (PPARGC1A) and MSCC (KIT). This latter association may suggest a biological link between the degree of piebaldism in Holstein and immunological functions affecting somatic cell count and mastitis resistance. Other significant SNPs were in the ACACA, CRH, CXCR1, FASN, GH1, LEP, LGB (also known as PAEP), MFGE8, SRC, TG, THRSP and TPH1 genes. These results provide information that can complement QTL mapping and genome‐wide association studies in Holstein.     

Identifying disease polymorphisms from case–control genetic association data

In case-control association studies, it is typical to observe several associated polymorphisms in a gene region. Often the most significantly associated polymorphism is considered to be the disease polymorphism; however, it is not clear whether it is the disease polymorphism or there is more than one disease polymorphism in the gene region. Currently, there is no method that can handle these problems based on the linkage disequilibrium (LD) relationship between polymorphisms. To distinguish real disease polymorphisms from markers in LD, a method that can detect disease polymorphisms in a gene region has been developed. Relying on the LD between polymorphisms in controls, the proposed method utilizes model-based likelihood ratio tests to find disease polymorphisms. This method shows reliable Type I and Type II error rates when sample sizes are large enough, and works better with re-sequenced data. Applying this method to fine mapping using re-sequencing or dense genotyping data would provide important information regarding the genetic architecture of complex traits.     

Searching new signals for production traits through gene‐based association analysis in three Italian cattle breeds

Genome‐wide association studies (GWAS) have been widely applied to disentangle the genetic basis of complex traits. In cattle breeds, classical GWAS approaches with medium‐density marker panels are far from conclusive, especially for complex traits. This is due to the intrinsic limitations of GWAS and the assumptions that are made to step from the association signals to the functional variations. Here, we applied a gene‐based strategy to prioritize genotype–phenotype associations found for milk production and quality traits with classical approaches in three Italian dairy cattle breeds with different sample sizes (Italian Brown n = 745; Italian Holstein n = 2058; Italian Simmental n = 477). Although classical regression on single markers revealed only a single genome‐wide significant genotype–phenotype association, for Italian Holstein, the gene‐based approach identified specific genes in each breed that are associated with milk physiology and mammary gland development. As no standard method has yet been established to step from variation to functional units (i.e., genes), the strategy proposed here may contribute to revealing new genes that play significant roles in complex traits, such as those investigated here, amplifying low association signals using a gene‐centric approach.     

Endothelial nitric oxide synthase gene polymorphisms (G894T, 4b/a and T-786C) and preeclampsia: meta-analysis of 18 case-control studies

Studies investigating the association between endothelial nitric oxide synthase (eNOS) gene polymorphisms and preeclampsia reported contradictory or nonconclusive results. We performed a meta-analysis of 18 genetic association studies that examined the relationship between preeclampsia and the G894T, 4a/b and T-786C polymorphisms of the eNOS gene. Subgroup analysis by ethnicity and potential sources of heterogeneity and bias were explored. The MEDLINE, EMBASE, and Google Scholar databases were searched to access the relevant genetic association studies up to June 2011. For the allelic analysis of the G894T variant, all studies showed no significant association. For the genotypic analysis, the combined studies of the G allele showed negative significance (odds ratio [OR]=0.56; 95% confidence interval [CI]: 0.33-0.97), all the studies showed positively significance when the T allele was combined (OR=1.17; 95% CI: 1.01-1.36), and results were also positively significant in non-Asian populations (OR=1.20; 95% CI: 1.02-1.43). For the allelic analysis of the 4b/a variant, all studies showed no significant association, but results were negatively significant in non-Asian populations (OR=0.67; 95% CI: 0.46-0.98). For the genotype analysis, combined studies of the b allele showed negative significance (OR=0.55; 95% CI: 0.36-0.84). Moreover, non-Asian studies showed negatively significant results (OR=0.45; 95% CI: 0.28-0.72). For the analysis of the T-786C variant, none of the studies showed significant results. The synthesis of available evidence supports the fact that intron 4a allele, homozygosity for the 894T and intron 4a of eNOS are positively associated with preeclampsia. Large, multiethnic confirmatory, and well-designed studies are needed to determine the relation between preeclampsia and polymorphisms of the eNOS gene.     

圈养梅花鹿BDNF基因多态性与日常行为性状的关联分析

采用目标动物取样法(Focal Animal Sampling)和全事件记录方法(All-occurrence Recording),观察统计了江苏省扬州市平山堂养殖场及扬州市动物园共48只梅花鹿昼间日常行为节律。以脑源性神经生长因子(Brain-derived Neurotrophic Factor, BDNF)为目的基因,采用PCR-SSCP方法,研究梅花鹿行为性状与基因多态性之间的关联。结果表明,在P-4引物,AA与BB基因型在卧息行为上存在显著差异(P<0.05),在运动行为上存在极显著差异(P=0.001)。在P-5引物,CC/DD/CD基因型在观望行为上两两差异显著,并且CC和DD基因型在卧息与修饰行为均存在显著差异(P<0.05)。研究表明,BDNF基因多态性和动物日常行为性状存在一定相关。     

Association of Hck genetic polymorphisms with gene expression and COPD

Polymorphonuclear leukocytes (PMNs) are major effector cells in the chronic airway inflammation in chronic obstructive pulmonary disease (COPD). PMN degranulation is associated with degradation of extracellular matrix and tissue damage. Hck is an essential molecule in the signaling pathway regulating PMN degranulation. We hypothesized that polymorphisms affect the expression level of Hck, which, in turn, modulates PMN mediator release and tissue damage and influences the development of COPD. Here we systematically investigated genetic tag polymorphisms of the Hck gene, Hck mRNA and protein expression pattern in PMNs, and PMN mediator release (myeloperoxidase) in 60 healthy white subjects, and assessed their association with the use of several genetic models. The association of genetic polymorphisms with COPD-related phenotypes was determined in the lung healthy study cohort (LHS). We identified a novel 15 bp insertion/deletion polymorphism (8,656 L/S) in intron 1 of the Hck gene, which was associated with differential expression of Hck protein and PMN myeloperoxidase release. In the LHS cohort, there was significant interaction between the 8,656 L/S polymorphism and smoking on baseline lung function and 8,656 L/S was associated with bronchodilator response. These data suggest that the insertion/deletion polymorphism could be a functional polymorphism of the Hck gene, may contribute to COPD pathogenesis and modify COPD-related phenotypes.     

Epigenetic variation predicts regional and local intraspecific functional diversity in a perennial herb

The ecological significance of epigenetic variation has been generally inferred from studies on model plants under artificial conditions, but the importance of epigenetic differences between individuals as a source of intraspecific diversity in natural plant populations remains essentially unknown. This study investigates the relationship between epigenetic variation and functional plant diversity by conducting epigenetic (methylation‐sensitive amplified fragment length polymorphisms, MSAP) and genetic (amplified fragment length polymorphisms, AFLP) marker–trait association analyses for 20 whole‐plant, leaf and regenerative functional traits in a large sample of wild‐growing plants of the perennial herb Helleborus foetidus from ten sampling sites in south‐eastern Spain. Plants differed widely in functional characteristics, and exhibited greater epigenetic than genetic diversity, as shown by per cent polymorphism of MSAP fragments (92%) or markers (69%) greatly exceeding that for AFLP ones (41%). After controlling for genetic structuring and possible cryptic relatedness, every functional trait considered exhibited a significant association with at least one AFLP or MSAP marker. A total of 27 MSAP (13.0% of total) and 12 AFLP (4.4%) markers were involved in significant associations, which explained on average 8.2% and 8.0% of trait variance, respectively. Individual MSAP markers were more likely to be associated with functional traits than AFLP markers. Between‐site differences in multivariate functional diversity were directly related to variation in multilocus epigenetic diversity after multilocus genetic diversity was statistically accounted for. Results suggest that epigenetic variation can be an important source of intraspecific functional diversity in H. foetidus, possibly endowing this species with the capacity to exploit a broad range of ecological conditions despite its modest genetic diversity.