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PubMed2001

Glycerol kinase deficiency: evidence for complexity in a single gene disorder.

Glycerol kinase deficiency (GKD) occurs as part of an Xp21 contiguous gene syndrome or as isolated GKD. The isolated form can be either symptomatic with episodic metabolic and central nervous system (CNS) decompensation or asymptomatic with hyperglycerolemia and glyceroluria only. To better understand the pathogenesis of isolated GKD, we sought individuals with point mutations in the GK coding region and measured their GK enzyme activities. We identified six individuals with missense mutations: four (N288D, A305V, M428T, and Q438R) among males who were asymptomatic and two (D198G, R405Q) in individuals who were symptomatic. GK activity measured in lymphoblastoid cell lines or fibroblasts was similar for the symptomatic and the asymptomatic individuals. Mapping of the individuals' missense mutations to the three-dimensional structure of Escherichia coli GK revealed that the symptomatic individuals' mutations are in the same region as a subset of the mutations among the asymptomatic individuals, adjacent to the active-site cleft. We conclude that, like many other disorders, GK genotype does not predict GKD phenotype. We hypothesize that the phenotype of an individual with GKD is a complex trait influenced by additional, independently inherited genes.

Catalytic Domain↗
PubMed2005

The future of pediatric nephrology.

The delineation of renal disease in children dates to the 1880s with descriptions of Henoch's purpura, bladder exstrophy, renal rickets and nephritis. The discipline of pediatric nephrology mainly emerged during the 20th century in response to problems in fluid and electrolyte balance, characterization of the nephrotic syndrome, use of renal biopsy, antibiotic therapy of urinary tract infections, dialysis and transplantation in children, growth problems associated with chronic renal failure, detection and therapy of hypertension, and the creation of both national and international pediatric nephrology societies and a journal now in its 18th year. The development of molecular and cell biology, genetic and genomic techniques and bioinformatics methods underlie many future directions. We should anticipate further elucidation of single gene disorders, of complex trait analysis of disorders, such as diabetic nephropathy and hypertension, the interplay of developmental genes and gene products and interactions within the podocyte. Specific therapies directed against inflammation, vascular damage, cyst development, the ravages of proteinuria and graft rejection (or induction leading to tolerance) will be developed. Stem cell therapies may replace lost renal mass, even of specific nephron sites. Novel therapies will also modulate the cell cycle, tyrosine kinase signaling and apoptosis. In addition, drugs will be specifically tested in children for many renal conditions. Larger and more specialized registries will be developed; epidemiologic studies and exploration of large data sets will lead to clinical guidelines that are evidenced-based. There is a need for more careful measurement of glomerular filtration rate (GFR), proteinuria and cytokines, and a fuller appreciation of the nutritional and hormonal role of the kidney. Finally, the antecedents of adult renal disease and the need to intervene in a proactive fashion will be realized. Despite these impressive advances in care, the greatest challenges will be in providing children with renal disease access to well-trained pediatric nephrologists, especially in Asia (1 billion children), Africa, Central and South America, and in immigrant and refugee populations. Included in this challenge is the capacity to have affordable access to use of contemporary techniques, and effective medications and prevention strategies. The International Pediatric Nephrology Association (IPNA), its journal, and pediatric advocates will need to use their energies to take on these challenges.

Child↗
PubMed2003

Dopamine D3 receptor gene polymorphism and violent behavior: relation to impulsiveness and ADHD-related psychopathology.

Several lines of evidence indicate that dopaminergic neurotransmission is involved in the regulation of impulsive aggression and violence and that genetically determined variability in dopaminergic gene expression modifies complex traits including that of impulsivity and aggression. In this study we report an association of the dopamine D3 receptor (DRD3) polymorphism with impulsiveness according to Eysenck's EIQ and scores on the German short version of the Wender Utah Rating Scale (WURS-k), which we used for the assessment of a history of ADHD-related symptoms. This association was detected in a group of violent offenders, but not in non-violent individuals. Highest scores of EIQ impulsiveness and of the WURS-k were found in heterozygous violent individuals, while homozygotes showed significant lower rating scores, suggesting an heterosis effect. The results of our study suggest that variations of the DRD3 gene are likely involved in the regulation of impulsivity and some psychopathological aspects of ADHD related to violent behavior.

Adult↗
PubMed2006

Assessment of linkage and association of 13 genetic loci with bone mineral density.

Bone mineral density (BMD), an important risk factor for osteoporosis, is a complex trait likely affected by multiple genes. The linkage and/or association of 13 polymorphic loci of seven candidate genes (estrogen receptor alpha [ERalpha] and beta [ERbeta], calcium-sensing receptor, vitamin D receptor, collagen type 1alpha1, low-density lipoprotein [LDL] receptor-related protein 5 [LRPS], and transforming growth factor beta1) were evaluated in 177 southern Chinese pedigrees of 674 subjects, with each pedigree identified through a proband having a BMD Z score of -1.28 or less at the hip or spine. A suggestive linkage was detected between the IVS1-351A/G polymorphism of ERalpha and spine BMD, and between the 1082G/A, 1730G/A, and D14S1026 polymorphisms of ERbeta and BMD at both spine and hip. The quantitative transmission disequilibrium test (QTDT) detected total family association between 1730G/A of ERbeta and BMD at spine and hip; between D14S1026 of ERbeta and hip BMD; and between the 266A/G and 2220C/T polymorphisms of LRP5 and hip BMD. Similar total family associations were detected when only the females were analyzed. In addition, the IVS1-397T/C polymorphism of ERalpha was associated with spine BMD, and the 266A/G and 2220C/T polymorphisms of LRP5 were associated with femoral neck BMD in the females. A within-family association was detected with the IVS1-397T/C polymorphism of ERalpha, and the 266A/G and 2220C/T polymorphisms of LRP5 in the females. The effect of each polymorphism on BMD variance ranged from 1% to 4%. In conclusion, ERalpha, ERbeta and LRP5 are important candidate genes determining BMD variation, especially in females.

Adult↗
PubMed2001

[Lip-jaw-palate clefts. Heterogenous disease pictures].

BACKGROUND: Orofacial clefts are congenital structural deficits involving the lip with or without the palate. The genetic origins of orofacial clefts have been considered as heterogeneous for a long time. Non-syndromatic clefts are based on complex traits. DISCUSSION: The different approaches towards the genetics of this multifactorial disease are discussed and the consequences for genetic counselling for patients, persons at risk and their relatives are reflected upon.

Adult↗
PubMed2001

Genetic susceptibility to MS: a second stage analysis in Canadian MS families.

Four published genome screens have identified a number of markers with increased sharing in multiple sclerosis (MS) families, although none has reached statistical significance. One hundred and five markers previously identified as showing increased sharing in Canadian, British, Finnish, and American genome screens were genotyped in 219 sibling pairs ascertained from the database of the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). No markers examined met criteria for significant linkage. Markers located at 5p14 and 17q22 were analyzed in a total of 333 sibling pairs and attained mlod scores of 2.27 and 1.14, respectively. The known HLA Class II DRB1 association with MS was confirmed (P<0.0001). Significant transmission disequilibrium was also observed for D17S789 at 17q22 (P=0.0015). This study highlights the difficulty of searching for genes with only mild-to-moderate effects on susceptibility, although large effects of specific loci may still be present in individual families. Future progress in the genetics of this complex trait may be helped by (1) focussing on more ethnically homogeneous samples, (2) using an increased number of MS families, and (3) using transmission disequilibrium analysis in candidate regions rather than the affected relative pair linkage analysis.

Canada↗
PubMed2004

Behavioral characterization of wild derived male mice (Mus musculus musculus) of the PWD/Ph inbred strain: high exploration compared to C57BL/6J.

PWD/Ph is an inbred mouse strain derived from wild mice trapped in central Czech Republic. These mice are of the Mus musculus musculus subspecies, whose ancestors separated from those of Mus musculus domesticus about one million years ago. There is a high degree of variation in the genomic sequence and a wide range of phenotypes between PWD/Ph and standard laboratory inbred mouse strains, the genomes of which are principally Mus musculus domesticus in origin, making PWD/Ph mice an useful resource for complex trait research. As a first step in taking advantage of this resource, a preliminary characterization of the behavior of PWD/Ph mice was performed. Groups of 10 PWD/Ph and C57BL/6J male mice were tested in the open field, novel object exploration task and Morris water maze. PWD/Ph were marginally more anxious than C57BL/6J mice in the open field but subsequently displayed much higher levels of exploration and lower anxiety than C57BL/6J mice following introduction of a novel object. As C57BL/6J itself is rated as highly explorative among classical inbred strains, PWD/Ph probably represents an extreme among mouse strains for this specific behavior. PWD/Ph and C57BL/6J mice differed in their water escape training profiles in the Morris water maze, perhaps reflecting different motivational factors. However, there were no differences in overall cognitive ability (spatial learning) as both groups learned to find the hidden platform and performed equally well when the location of the platform was changed. This is the first quantification of the behavior of PWD/Ph mice and the results are promising for the potential of the consomic panel currently being generated with PWD/Ph and C57BL/6J as a tool for the molecular dissection of behavior.

Animals↗
PubMed2005

Genetic and environmental contributions to loneliness in adults: the Netherlands twin register study.

Heritability estimates based on two small studies in children indicate that the genetic contribution to individual differences in loneliness is approximately 50%. Heritability estimates of complex traits such as loneliness may change across the lifespan, however, as the frequency, duration, and range of exposure to environmental influences accrues, or as the expression of genetic factors changes. We examined data on loneliness from 8,387 young adult and adult Dutch twins who had participated in longitudinal survey studies. A measure of loneliness was developed based on factor analyses of items of the YASR (The Young Adult Self Report). Variation in loneliness was analyzed with genetic structural equation models. The estimate of genetic contributions to variation in loneliness in adults was 48%, which is similar to the heritability estimates found previously in children. There was no evidence for sex or age differences in genetic architecture. Sex differences in prevalence were significant, but we did not see an association with age or birth cohort. All resemblance between twin relatives was explained by shared genes, without any suggestion of a contribution of shared environmental factors.

Adult↗
PubMed2006

Design and analysis of association studies using pooled DNA from large twin samples.

Evidence is mounting that multiple genes are involved in complex traits and that these each account for very small proportions of the overall phenotypic variance. Association studies of many markers in 1000s of individuals will be required to identify such genes. A number of large twin cohorts have already been collected and provide a valuable resource for carrying out studies that are robust to the effect of population stratification. Technologies based on microarrays will soon allow 1.000,000 SNPs to be typed at one time, however financial considerations prevent most researchers from using these approaches to genotype all individuals. Recently, microarrays have been shown to give accurate allele frequency measurements in pooled DNA samples and provide a simple way to select the best markers for individual genotyping. This drastically reduces the cost and workload of large scale association studies. One limitation of this methodology relates to the analytical procedures which have only been developed to allow comparison of two pools e.g. case/control pools. In this paper we use meta-regression to analyze pooled DNA data allowing the allele frequency in each pool to be related to the average quantitative phenotypic measure of the individuals whose DNA were used to construct the pools. Alongside this we describe a technique that can be used to determine the power for such studies. We present results from some preliminary investigations of different pooling strategies that can be applied to large twin samples and demonstrate that the method retains a large proportion of the power available from individual genotyping.

Computer Simulation↗
PubMed2005

A natural diet versus modern Western diets? A new approach to prevent "well-being syndromes".

Obesity is the most common nutritional disorder in the Western world. Actually, 250 million adults are obese, and 500 million adults and 22 million children under 5 years of age are overweight. Obesity is a complex trait, depending upon interactions between multiple genes and the environment, but its recent rise and "epidemic proportions" are, above all, the consequences of dramatic changes in lifestyle, socioeconomic progress, and political and cultural trends. Eating behavior has strong extraphysiological determinants, being influenced by neuroendocrine, nutritional, environmental, and cognitive stimuli, able to modify the body weight set-point. Health care professionals should be concerned about obesity, because of the well-established relations between excess body weight and pathologies such as type II diabetes, hypertension, atherosclerosis, osteoarthritis, dyslipidemia, and cancer, which afflict more and more people in the Western world--sort of "well-being syndromes." An overview of modern Western diets--the American, Mediterranean, Atkins, and Zone diets--reveals the contradictions existing about the correct and healthy approach to human nutrition and suggests a "return to Nature." From the actual artificial nutrition systems, based on cereals, milk, and their products, irrespective of our genome and metabolic attitudes, a simple diet based on natural food can be an ally in health maintenance and restoration.

Cardiovascular Diseases↗
PubMed2005

Testing hypotheses regarding the genetics of adaptation.

Many of the hypotheses regarding the genetics of adaptation require that one know specific details about the genetic basis of complex traits, such as the number and effects of the loci involved. Developments in molecular biology have made it possible to create relatively dense maps of markers that can potentially be used to map genes underlying specific traits. However, there are a number of reasons to doubt that such mapping will provide the level of resolution necessary to specifically address many evolutionary questions. Moreover, evolutionary change is built upon the substitution of individual mutations, many of which may now be cosegregating in the same allele. In order for this developing area not to become a mirage that traps the efforts of an entire field, the genetic dissection of adaptive traits should be conducted within a strict hypothesis-testing framework and within systems that promise a reasonable chance of identifying the specific genetic changes of interest. Continuing advances in molecular technology may lead the way here, but some form of genetic testing is likely to be forever required.

Adaptation, Biological↗
PubMed2004

Diet and low-density lipoprotein particle size.

Small, dense low-density lipoprotein (LDL) particles are being increasingly recognized as an important risk factor for cardiovascular disease. This paper provides an overview of how different diets and macronutrients modulate the LDL size phenotype. Data reviewed indicated that several components of the LDL size phenotype should be measured concurrently in order to fully appreciate the impact of diet on this complex trait. Data also suggested that numerous dietary elements have a significant impact on several characteristics of the LDL size phenotype, thus providing further evidence to the concept that specific dietary modifications can beneficially alter cardiovascular disease risk beyond their known and demonstrated effects on plasma LDL cholesterol concentrations.

Cardiovascular Diseases↗
PubMed2005

Coronary heart disease and polymorphisms in genes affecting lipid metabolism and inflammation.

Several biologic systems contribute to the pathophysiology of atherosclerosis and its complications, and within each of these systems many genes have been explored to establish the possible implication of their variability in coronary heart disease (CHD) risk. This report is focused on recent results pertaining to lipid and inflammatory genes, their variability, and their relationship with intermediate phenotypes and CHD. For both systems, there is no evidence at the present time that testing genetic polymorphisms might be of any benefit to the patient, for the diagnosis or prognosis of CHD, or for tailoring drug prescription. Understanding the genetics of complex traits like CHD will require a system approach that allows a modeling of the interaction among genes as well as between genetic and nongenetic sources of variation.

Coronary Disease↗
PubMed1994

Association studies in multiple sclerosis.

In the search for candidate loci having a role in susceptibility to common diseases such as multiple sclerosis (MS), studies often look for an 'association' between one allele at a putative candidate susceptibility locus and the disease, e.g. MS. However, reproducibility of results from association studies has been difficult. In MS, despite numerous studies, association has been reproducibly confirmed only for the major histocompatibility complex, the MHC. The present paper is designed to review the allelic associations which have been reported in MS and suggest possible reasons for the difficulties in replicating these studies. We also outline some suggestions for improving the validity of future association studies in MS and in other complex traits.

Alleles↗
PubMed1995

Comparative maps: the mammalian jigsaw puzzle.

Chromosomal rearrangements such as inversions and translocations have played an important role in defining genome organization in existing mammals. The number of rearrangements that have occurred since divergence from the 'primordial' mammal has been modest and the distribution of these rearrangements among chromosomes seems to be random. As a result, each mammalian species has a unique arrangement of conserved and disrupted chromosomal segments as compared to other mammalian species. Genes are excellent markers for these chromosomal segments because homologies can be detected in highly divergent species. By comparing the chromosomal location of homologous genes in different species, maps of conserved chromosomal segments can be obtained. These comparative maps can be used to predict gene locations in other species, identify candidate disease genes, characterize the genetic basis for complex traits, and find modulators of disease susceptibility. Equally important is the use of comparative maps for addressing questions about genome organization and evolution.

Animals↗
PubMed2026

Shared genetic basis and structure of syndromic and normal facial variation.

The question of how gene mutations of large effect and common variants of small effect relate to phenotypic variation dates from the origins of genetics. Mendelian diseases result from rare germline variants with major effects, while complex traits are associated with multiple, mostly common variants of small effect. High-dimensional phenotypes, such as facial shape, can shed new light on this age-old dichotomy, as their variation can be characterized in terms of directions in multivariate morphospace. Within such spaces, do Mendelian disease mutations move phenotypes along the same directions as common variants, or do they forge new directions that diverge from the common structure of background variation? Here, we analyze facial shape variation for 66 syndromes, quantify multivariate axes of facial shape variation for each syndrome, and test whether common genetic variants in cohorts of non-syndromic subjects are associated with phenotypic position along these same axes. We find that syndromic facial shape generally follows the background variance-covariance structure of facial shape in the general population. Furthermore, syndromic probands' unaffected relatives have subtle facial morphology resembling the syndromes of their affected relatives. These results suggest that Mendelian disease variants act on facial shape in ways similar to common variants. Syndromic probands with higher "severity" likely occur on genetic backgrounds with higher cumulative severity of common variants for each syndromic axis. These findings position Mendelian diseases at extremes along phenotypic continua that exist in the background population rather than as qualitatively different phenotypes distinct from the overall structure of normal human phenotypic variation.

Humans↗
PubMed2006

Meta-analysis of genome-wide scans for blood pressure in African American and Nigerian samples. The National Heart, Lung, and Blood Institute GeneLink Project.

BACKGROUND: In many genetic studies of complex traits, sample sizes are often too small to detect linkages of low-to-moderate effects. However, the combined linkage evidence across several studies can be synthesized using meta-analysis with the aim of providing more definitive support of linkage. METHODS: In the current study using the National Heart, Lung, and Blood Institute (NHLBI) GeneLink Project, a meta-analysis based on a modification of Fisher's method of pooling P values was used to investigate linkage for systolic blood pressure (SBP) and diastolic blood pressure (DBP) values across three studies involving African American and Nigerian families (HyperGEN, Health, Risk Factors, Exercise Training and Genetics [HERITAGE], and Genetics of Hypertension in Blacks). RESULTS: The meta results suggest two regions (2p and 7p) provide enhanced linkage evidence compared with the individual study results. The maximal meta Lod score of 2.9 on 2p14-p13.1 (64-78 cM) represented approximately 1-Lod unit increase over the respective individual study scores. This general region has been implicated previously involving primarily families of white ethnicity and provides confirmatory evidence that this QTL is common across ethnic groups. The second finding at 7p21.3-p15.3 (8-25 cM) provided a meta Lod of 3.5. Although region was implicated primarily in the Nigerian subjects the low-level but consistent support involving the African American families (individual Lod score of 1.0) suggests a novel QTL with respect to BP variation in individuals of black ethnicity. CONCLUSIONS: Follow-up studies involving positional cloning efforts of the combined families showing linkage evidence in these regions (particularly 2p) may be warranted to verify these findings and identify the genes and causative variants.

Adolescent↗
PubMed2005

Design and analysis in genetic studies of human ageing and longevity.

With the success of the Human Genome Project and taking advantage of the recent developments in high-throughput genotyping techniques as well as in functional genomics, it is now feasible to collect vast quantities of genetic data with the aim of deciphering the genetics of human complex traits. As a result, the amount of research on human ageing and longevity has been growing rapidly in recent years. The situation raises questions concerning efficient choice of study population, sampling schemes, and methods of data analysis. In this article, we summarize the key issues in genetic studies of human ageing and longevity ranging from research design to statistical analyses. We discuss the virtues and drawbacks of the multidisciplinary approaches including the population-based cross-sectional and cohort studies, family-based linkage analysis, and functional genomics studies. Different analytical approaches are illustrated with their performances compared. In addition, important research topics are highlighted together with experiment design and data analyzing issues to serve as references for future studies.

Aging↗