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Intermediate Phenotype (intermediate + phenotype)
Selected AbstractsVariance components analyses of multiple asthma traits in a large sample of Australian families ascertained through a twin probandALLERGY, Issue 2 2006M. A. R. Ferreira Background:, Intermediate phenotypes are often measured as a proxy for asthma. It is largely unclear to what extent the same set of environmental or genetic factors regulate these traits. Objective:, Estimate the environmental and genetic correlations between self-reported and clinical asthma traits. Methods:, A total of 3073 subjects from 802 families were ascertained through a twin proband. Traits measured included self-reported asthma, airway histamine responsiveness (AHR), skin prick response to common allergens including house dust mite (Dermatophagoides pteronyssinus [D. pter]), baseline lung function, total serum immunoglobulin E (IgE) and eosinophilia. Bivariate and multivariate analyses of eight traits were performed with adjustment for ascertainment and significant covariates. Results:, Overall 2716 participants completed an asthma questionnaire and 2087 were clinically tested, including 1289 self-reported asthmatics (92% previously diagnosed by a doctor). Asthma, AHR, markers of allergic sensitization and eosinophilia had significant environmental correlations with each other (range: 0.23,0.89). Baseline forced expiratory volume in 1 s (FEV1) showed low environmental correlations with most traits. Fewer genetic correlations were significantly different from zero. Phenotypes with greatest genetic similarity were asthma and atopy (0.46), IgE and eosinophilia (0.44), AHR and D. pter (0.43) and AHR and airway obstruction (,0.43). Traits with greatest genetic dissimilarity were FEV1 and atopy (0.05), airway obstruction and IgE (0.07) and FEV1 and D. pter (0.11). Conclusion:, These results suggest that the same set of environmental factors regulates the variation of many asthma traits. In addition, although most traits are regulated to great extent by specific genetic factors, there is still some degree of genetic overlap that could be exploited by multivariate linkage approaches. [source] Exploiting human anatomical variability as a link between genome and cognomeGENES, BRAIN AND BEHAVIOR, Issue S1 2006C. M. Leonard Although talents and disabilities appear to run in families, direct links between genes and cognitive ability are difficult to establish. Investigators are currently searching for intermediate phenotypes with plausible links to both genome and cognome (the cognitive phenotype). Cortical anatomy could provide one such intermediate phenotype. Variation in cortical size, asymmetry and sulcal pattern is influenced by genetic variation in neurotrophic factors and can predict variation in verbal and mathematical talent. Anecdotal evidence suggests that individuals with a rare morphological variant of Sylvian fissure sometimes have superior visualization ability combined with verbal deficits. Documentation of such ,cognitive cortical syndromes' might prove as genetically informative as the identification of dysmorphic syndromes associated with mental retardation. A necessary prerequisite for the establishment of such syndromes is a reliable technique for the identification of cortical patterns. Recent technical advances in software for automatically labeling and measuring cortical sulci now provide the possibility of establishing standard measures for their shape, size and location. Such measures are a prerequisite for genetic studies of cortical patterns that could illuminate the neurodevelopmental pathways by which genes affect cognitive ability. [source] Magnetoencephalographic gamma power reduction in patients with schizophrenia during resting conditionHUMAN BRAIN MAPPING, Issue 10 2009Lindsay Rutter Abstract Objective: The "default network" represents a baseline condition of brain function and is of interest in schizophrenia research because its component brain regions are believed to be aberrant in the disorder. We hypothesized that magnetoencephalographic (MEG) source localization analysis would reveal abnormal resting activity within particular frequency bands in schizophrenia. Experimental Design: Eyes-closed resting state MEG signals were collected for two comparison groups. Patients with schizophrenia (N = 38) were age-gender matched with healthy control subjects (N = 38), and with a group of unmedicated unaffected siblings of patients with schizophrenia (N = 38). To localize 3D-brain regional differences, synthetic aperture magnetometry was calculated across established frequency bands as follows: delta (0.9,4 Hz), theta (4,8 Hz), alpha (8,14 Hz), beta (14,30 Hz), gamma (30,80 Hz), and super-gamma (80,150 Hz). Principle Observations: Patients with schizophrenia showed significantly reduced activation in the gamma frequency band in the posterior region of the medial parietal cortex. As a group, unaffected siblings of schizophrenia patients also showed significantly reduced activation in the gamma bandwidth across similar brain regions. Moreover, using the significant region for the patients and examining the gamma band power gave an odds ratio of 6:1 for reductions of two standard deviations from the mean. This suggests that the measure might be the basis of an intermediate phenotype. Conclusions: MEG resting state analysis adds to the evidence that schizophrenic patients experience this condition very differently than healthy controls. Whether this baseline difference relates to network abnormalities remains to be seen. Hum Brain Mapp, 2009. © 2009 Wiley-Liss, Inc. [source] Neural connectivity as an intermediate phenotype: Brain networks under genetic controlHUMAN BRAIN MAPPING, Issue 7 2009Andreas Meyer-Lindenberg Abstract Recent evidence suggests that default mode connectivity characterizes neural states that account for a sizable proportion of brain activity and energy expenditure, and therefore represent a plausible neural intermediate phenotype. This implies the possibility of genetic control over systems-level connectivity features. Imaging genetics is an approach to combine genetic assessment with multimodal neuroimaging to discover neural systems linked to genetic abnormalities or variation. In the present contribution, we report results obtained from applying this strategy to both structural connectivity and functional connectivity data. Using data for serotonergic (5-HTTLPR, MAO-A) and dopaminergic (DARPP-32) genes as examples, we show that systems-level connectivity networks under genetic control can be identified. Remarkable similarities are observed across modalities and scales of description. Features of connectivity often better account for behavioral effects of genetic variation than regional parameters of activation or structure. These data provide convergent evidence for genetic control in humans over connectivity systems, whose characterization has promise for identifying neural systems mediating genetic risk for complex human behavior and psychiatric disease. Hum Brain Mapp, 2009. © 2009 Wiley-Liss, Inc. [source] Idiopathic Hyperphosphatasia and TNFRSF11B Mutations: Relationships Between Phenotype and Genotype,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2003Belinda Chong Abstract Homozygous mutations in TNFRSF11B, the gene encoding osteoprotegerin, were found in affected members from six of nine families with idiopathic hyperphosphatasia. The severity of the phenotype was related to the predicted effects of the mutations on osteoprotegerin function. Introduction: Idiopathic hyperphosphatasia (IH) is a rare high bone turnover congenital bone disease in which affected children are normal at birth but develop progressive long bone deformities, fractures, vertebral collapse, skull enlargement, and deafness. There is, however, considerable phenotypic variation from presentation in infancy with severe progressive deformity through to presentation in late childhood with minimal deformity. Two recent reports have linked idiopathic hyperphosphatasia with deletion of, or mutation in, the TNFRSF11B gene that encodes osteoprotegerin (OPG), an important paracrine modulator of RANKL-mediated bone resorption. Materials and Methods: We studied subjects with a clinical diagnosis of IH and unaffected family members from nine unrelated families. Clinical, biochemical, and radiographic data were collected, and genomic DNA examined for mutations in TNFRSF11B. The relationship between the mutations, their predicted effects on OPG function, and the phenotype were then examined. Results: Of the nine families studied, affected subjects from six were homozygous for novel mutations in TNFRSF11B. Their parents were heterozygous, consistent with autosomal recessive inheritance. Four of the six mutations occurred in the cysteine-rich ligand-binding domain and are predicted to disrupt binding of OPG to RANKL. Missense mutations in the cysteine residues, predicted to cause major disruption to the ligand-binding region, were associated with a severe phenotype (deformity developing before 18 months age and severe disability), as was a large deletion mutation. Non-cysteine missense mutations in the ligand-binding domain were associated with an intermediate phenotype (deformity recognized around the age of 5 years and an increased rate of long bone fracture). An insertion/deletion mutation at the C-terminal end of the protein was associated with the mildest phenotype. Conclusion: Mutations in TNFRSF11B account for the majority of, but not all, cases of IH, and there are distinct genotype-phenotype relationships. [source] Hybrid incompatibility is consistent with a hybrid origin of Heliconius heurippa Hewitson from its close relatives, Heliconius cydno Doubleday and Heliconius melpomene LinnaeusJOURNAL OF EVOLUTIONARY BIOLOGY, Issue 2 2005C. A. Salazar Abstract Shared ancestral variation and introgression complicates the reconstruction of phylogenetic relationships among closely related taxa. Here we use overall genomic compatibility as an alternative estimate of species relationships in a group where divergence is rapid and genetic exchange is common. Heliconius heurippa, a butterfly species endemic to Colombia, has a colour pattern genetically intermediate between H. cydno and H. melpomene: its hindwing is nearly indistinguishable from that of H. melpomene and its forewing band is an intermediate phenotype between both species. This observation has lead to the suggestion that the pattern of H. heurippa arose through hybridization. We present a genetic analysis of hybrid compatibility in crosses between the three taxa. Heliconius heurippa × H. cydno and female H. melpomene × male H. heurippa yield fertile and viable F1 hybrids, but male H. melpomene × female H. heurippa crosses yield sterile F1 females. In contrast, Haldane's rule has previously been detected between H. melpomene and H cydno in both directions. Therefore, H. heurippa is most closely related to H. cydno, with some evidence for introgression of genes from H. melpomene. The results are compatible with the hypothesis of a hybrid origin for H. heurippa. In addition, backcrosses using F1 hybrid males provide evidence for a large Z(X)-chromosome effect on sterility and for recessive autosomal sterility factors as predicted by Dominance Theory. [source] Morphology,diet relationships in four killifishes (Teleostei, Cyprinodontidae, Orestias) from Lake TiticacaJOURNAL OF FISH BIOLOGY, Issue 3 2009E. Maldonado This study explores the relationship between morphology and diet in four Andean killifishes (Orestias) from Lake Titicaca that are known to differ in habitat use. Species that fed preferentially on amphipods (Orestias albus) or molluscs (Orestias luteus) separated in multivariate space from other species that feed on cladocera and algae (Orestias agassii and Orestias jussiei). Generally, specimens feeding on cladocera were characterized by a short, blunt nose with a small mouth; whereas, specimens feeding on amphipods exhibited a long snout with a large mouth. Specimens including molluscs in their diet tended to have a larger posterior part of the head and the larger opercles than others; while the occurrence of substratum in gut content was generally related to a short but deep head. The present analysis suggests that the littoral O. jussiei has an intermediate phenotype and diet between the pelagic (O. agassii) and benthic (O. albus and O. luteus) species. Results suggest that resource partitioning was occurring and that several morphological traits relate to characteristics of the diet, and it is inferred that the benthic, the pelagic and the littoral zones in the lake host different prey communities constituting distinct adaptive landscapes. [source] An Expanded Evaluation of the Relationship of Four Alleles to the Level of Response to Alcohol and the Alcoholism RiskALCOHOLISM, Issue 1 2005Xianzhang Hu Background: Alcoholism is a complex, genetically influenced disorder the cause of which may be better understood through the study of genetically influenced phenotypes that mediate the risk. One such intermediate phenotype is the low level of response (LR) to alcohol. This project used a case-control approach to search for genes that may contribute to LR. Methods: Data were available from alcohol challenges at approximately age 20 and regarding the development of alcohol use disorders over the subsequent 20 years for 85 men, including 40 reported in a previous genetic analysis. LR was evaluated using oral consumption of 0.75 ml/kg of alcohol, after which changes in subjective feelings of intoxication and body sway were measured. Alcohol abuse and dependence were diagnosed by DSM-III-R criteria through structured interviews administered to both the participant and an informant (usually the spouse) 10, 15, and 20 years after initial testing. Four polymorphisms were evaluated, including the serotonin transporter HTTLPR promoter ins/del, GABAA,6 Pro385Ser, NPY Leu7Pro, and catalase 262C>T. Two of these, HTTLPR and GABAA,6 Pro385Ser, had been previously associated with LR and alcoholism in a preliminary study. Results: The HTTLPR L allele was significantly related to both the LR and alcoholism in an allele-dosage (stepwise) manner. Furthermore, the association remained when L alleles were subdivided into recently reported functional subtypes: the lowest LR was associated with genotypes correlated with the highest serotonin transporter expression. The GABAA,6 Ser385 allele showed a nonsignificant trend for association to a low LR, as had been previously observed, although the Ser385 allele is uncommon, and only 18 heterozygotes were in the current group. However, the six men with both LL and Pro385/Ser385 genotypes had the lowest LR, and each had developed alcoholism during follow-up. Neither NPY nor catalase was associated with either LR or alcoholic outcomes, although the sample did not have sufficient power for definitive conclusions. Conclusions: This report strengthens the support for a relationship between the HTTLPR L and GABAA,6 Ser385 alleles to low alcohol LR and to alcoholism in a prospectively studied cohort evaluated for LR in young adulthood and before the onset of alcohol dependence. [source] A phylogeographic analysis of southern and eastern populations of the Australian magpie: evidence for selection in maintenance of the distribution of two plumage morphsBIOLOGICAL JOURNAL OF THE LINNEAN SOCIETY, Issue 1 2001J. M. HUGHES The Australian magpie (Gymnorhina tibicen) is polymorphic for back colour with three distinct morphs recognized: the black-backed form (BB) which occurs in northern and north-eastern Australia; the white-backed form (WB) which occurs in south-eastern Australia and Tasmania and the Western form which occurs in the far south-west corner of the continent. Male and female WBs and BBs are both monomorphic for back colour while Westerns are sexually dimorphic, with males white-backed and females black-backed. In the south-east the WB and BB distributions overlap with individuals of intermediate phenotype interspersed with pure WB and BB phenotypes. This study used mtDNA control-region sequences to test the predictions of two alternative hypotheses to explain the distribution of WB and BB populations in eastern Australia and Tasmania. Our data support the hypothesis that the variation has evolved in situ, as no population genetic structuring was evident in eastern Australia related to back colour and Tasmanian WBs were no more closely related to mainland WBs than to mainland BBs (primary contact hypothesis). Back colour patterns may be maintained by different forms of natural selection favouring BB genes in the north-east and WB genes in the south-east. [source] Aldosterone synthase gene variation and adrenocortical response to sodium status, angiotensin II and ACTH in normal male subjectsCLINICAL ENDOCRINOLOGY, Issue 2 2004Brian Kennon Summary objective, Aldosterone synthase, a key enzyme in the terminal steps of aldosterone synthesis, is encoded by the CYP11B2 gene. A polymorphism in the 5, coding region of this gene (,344 C/T) is associated with hypertension, particularly with elevation of the aldosterone to renin ratio. A second polymorphism (a conversion in intron 2 to resemble that of the neighbouring 11,-hydroxylase (CYP11B1) gene) is found in close linkage dysequilibrium with the variant at ,344 C/T. The mechanism by which these variants predispose to cardiovascular disease and the precise intermediate phenotype associated with them remains speculative. design, We performed a focused physiological study in normal volunteers stratified by CYP11B2 genotype. patients, Twenty-three subjects homozygous for the T allele and 21 homozygous for the C allele of the ,344 C/T polymorphism of CYP11B2 were studied. measurements, Basal and angiotensin II stimulated plasma and 24-h urinary steroid excretion during low (60 mmol/day) and high (160 mmol/day) sodium intake and plasma steroids after ACTH stimulation were measured. results, No influence of polymorphic variation on basal or stimulated plasma cortisol or aldosterone or other plasma steroid concentrations during either dietary phase was seen. However, excretion of tetrahydro-11-deoxycortisol (the urinary metabolite of 11-deoxycortisol), which is the precursor of cortisol) was increased in TT subjects during sodium restriction, consistent with impairment of zona fasciculata 11,-hydroxylation. conclusions, We conclude that this polymorphism has no major influence on normal zona glomerulosa function but is associated with a change in 11,-hydroxylation in the zona fasciculata. The mechanism remains uncertain, but alteration of 11-deoxycortisol levels without change in cortisol suggests altered efficiency of 11,-hydroxylation. In the long term, this may lead to a minor but chronic increase in ACTH drive to the gland, which may have consequences for steroid synthesis and predispose to the risk of cardiovascular disease. [source] Candidate gene studies in the 21st century: meta-analysis, mediation, moderationGENES, BRAIN AND BEHAVIOR, Issue S1 2006M. R. Munafò The results of a large body of candidate gene studies of behavioural and psychiatric phenotypes have been largely inconclusive, with most findings failing to replicate reliably. A variety of approaches that augment the ,traditional' candidate gene approach are discussed, including the use of meta-analysis to combine findings from existing published reports, the investigation of mediating variables (including the use of intermediate phenotypes or endophenotypes) and the awareness of possible moderating influences (such as sex or ethnicity) and gene,environment interactions on genetic associations, possibly via epigenetic mechanisms. Advances in genotyping technology will also allow the routine use of haplotype analysis and linkage disequilibrium mapping. Examples of how these approaches may improve our understanding of how genetic associations with behavioural and psychiatric phenotypes obtain are given. [source] Exploiting human anatomical variability as a link between genome and cognomeGENES, BRAIN AND BEHAVIOR, Issue S1 2006C. M. Leonard Although talents and disabilities appear to run in families, direct links between genes and cognitive ability are difficult to establish. Investigators are currently searching for intermediate phenotypes with plausible links to both genome and cognome (the cognitive phenotype). Cortical anatomy could provide one such intermediate phenotype. Variation in cortical size, asymmetry and sulcal pattern is influenced by genetic variation in neurotrophic factors and can predict variation in verbal and mathematical talent. Anecdotal evidence suggests that individuals with a rare morphological variant of Sylvian fissure sometimes have superior visualization ability combined with verbal deficits. Documentation of such ,cognitive cortical syndromes' might prove as genetically informative as the identification of dysmorphic syndromes associated with mental retardation. A necessary prerequisite for the establishment of such syndromes is a reliable technique for the identification of cortical patterns. Recent technical advances in software for automatically labeling and measuring cortical sulci now provide the possibility of establishing standard measures for their shape, size and location. Such measures are a prerequisite for genetic studies of cortical patterns that could illuminate the neurodevelopmental pathways by which genes affect cognitive ability. [source] Combining fMRI and SNP data to investigate connections between brain function and genetics using parallel ICA,HUMAN BRAIN MAPPING, Issue 1 2009Jingyu Liu Abstract There is current interest in understanding genetic influences on both healthy and disordered brain function. We assessed brain function with functional magnetic resonance imaging (fMRI) data collected during an auditory oddball task,detecting an infrequent sound within a series of frequent sounds. Then, task-related imaging findings were utilized as potential intermediate phenotypes (endophenotypes) to investigate genomic factors derived from a single nucleotide polymorphism (SNP) array. Our target is the linkage of these genomic factors to normal/abnormal brain functionality. We explored parallel independent component analysis (paraICA) as a new method for analyzing multimodal data. The method was aimed to identify simultaneously independent components of each modality and the relationships between them. When 43 healthy controls and 20 schizophrenia patients, all Caucasian, were studied, we found a correlation of 0.38 between one fMRI component and one SNP component. This fMRI component consisted mainly of parietal lobe activations. The relevant SNP component was contributed to significantly by 10 SNPs located in genes, including those coding for the nicotinic ,-7cholinergic receptor, aromatic amino acid decarboxylase, disrupted in schizophrenia 1, among others. Both fMRI and SNP components showed significant differences in loading parameters between the schizophrenia and control groups (P = 0.0006 for the fMRI component; P = 0.001 for the SNP component). In summary, we constructed a framework to identify interactions between brain functional and genetic information; our findings provide a proof-of-concept that genomic SNP factors can be investigated by using endophenotypic imaging findings in a multivariate format. Hum Brain Mapp, 2009. © 2007 Wiley-Liss, Inc. [source] How do natural and sexual selection contribute to sympatric speciation?JOURNAL OF EVOLUTIONARY BIOLOGY, Issue 6 2004S. Gourbiere Abstract I use explicit genetic models to investigate the importance of natural and sexual selection during sympatric speciation and to sort out how genetic architecture influences these processes. Assortative mating alone can lead to speciation, but rare phenotypes' disadvantage in finding mates and intermediate phenotypes' advantage due to stabilizing selection strongly impede speciation. Any increase in the number of loci also decreases the likelihood of speciation. Sympatric speciation is then harder to achieve than previously demonstrated by many theoretical studies which assume no mating disadvantage for rare phenotypes and consider a small number of loci. However, when a high level of assortative mating evolves, sexual selection might allow populations to split into dimorphic distributions with peaks corresponding to nearly extreme phenotypes. Competition then works against speciation by favouring intermediate phenotypes and preventing further divergence. The interplay between natural and sexual selection during speciation is then more complex than previously explained. [source] Brain oscillations forever , neurophysiology in future research of child psychiatric problemsTHE JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY AND ALLIED DISCIPLINES, Issue 1-2 2009Aribert Rothenberger For decades neurophysiology has successfully contributed to research and clinical care in child psychiatry. Recently, methodological progress has led to a revival of interest in brain oscillations (i.e., a band of periodic neuronal frequencies with a wave-duration from milliseconds to several seconds which may code and decode information). These oscillations will nurture future information processing research during normal and pathological brain development, allowing us to investigate basic neuronal connectivity as well as interactions of brain systems and their modulation (e.g., by temporal neuronal synchronisation) as close correlates of behaviour and intermediate phenotypes from genes to behavioural variations. Especially, a systematic neurodynamic look at transitional processes from rest to stimulus-triggered goal-directed performance will aid behavioural understanding and guidance of children. Preliminary data suggest two separate oscillatory mechanisms in this respect. One is ongoing from pre- to post-stimulus processing and related to quantitative modification of behaviour, while another is merely related to qualitative effects of behaviour and reflects ,on-top' post-stimulus processing by temporal neuronal synchronisation of the oscillatory network in question. Suggested neurodynamic models may be tested in multilevel clinical experiments as well as in the framework of computational neuropsychiatry. [source] Congenic Rats For Hypertension: How Useful Are They For The Hunting Of Hypertension Genes?CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2000Toru Nabika SUMMARY 1. Linkage studies have revealed quantitative trait loci (QTL) for blood pressure in the rat genome using genetic hypertensive rat models. To identify the genes responsible for hypertension, the construction of congenic rats is essential. 2. To date, several congenic strains have been obtained from spontaneously hypertensive or Dahl salt-sensitive rats. The results of these studies should be interpreted according to whether the rats carry the whole QTL region or not. 3. After establishing congenic strains, three strategies are possible: (i) an orthodox positional cloning in which, using subcongenic strains, the QTL region is cut down to smaller fragments suitable for physical mapping; (ii) a positional candidate strategy in which candidate genes in the QTL regions are studied; or (iii) physiological studies in which intermediate phenotypes directly associated with the hypertension gene are explored. Several other experimental strategies are also available using congenic strains as new animal models for hypertension. 4. To make the most of advances in DNA technology, the precise evaluation of the phenotypic difference between congenic strains carrying different QTL or between a congenic and parental strain is critical. [source] | |||||||||||||||||||||||||