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PubMed2004

Linkage analysis of psychosis in bipolar pedigrees suggests novel putative loci for bipolar disorder and shared susceptibility with schizophrenia.

The low-to-moderate resolution of linkage analysis in complex traits has underscored the need to identify disease phenotypes with presumed genetic homogeneity. Bipolar disorder (BP) accompanied by psychosis (psychotic BP) may be one such phenotype. We previously reported a genome-wide screen in a large bipolar pedigree sample. In this follow-up study, we reclassified the disease phenotype based on the presence or absence of psychotic features and subgrouped pedigrees according to familial load of psychosis. Evidence for significant linkage to psychotic BP (genome-wide P<0.05) was obtained on chromosomes 9q31 (lod=3.55) and 8p21 (lod=3.46). Several other sites were supportive of linkage, including 5q33 (lod=1.78), 6q21 (lod=1.81), 8p12 (lod=2.06), 8q24 (lod=2.01), 13q32 (lod=1.96), 15q26 (lod=1.96), 17p12 (lod=2.42), 18q21 (lod=2.4), and 20q13 (lod=1.98). For most loci, the highest lod scores, including those with genome-wide significance (at 9q31 and 8p21), occurred in the subgroup of families with the largest concentration of psychotic individuals (> or =3 in a family). Interestingly, all regions but six--5q33, 6q21, 8p21, 8q24, 13q32 and 18q21--appear to be novel; namely, they did not show notable linkage to BP in other genome scans, which did not employ psychosis for disease classification. Also of interest is possible overlap with schizophrenia, another major psychotic disorder: seven of the regions presumed linked in this study--5q, 6q, 8p, 13q, 15q, 17p, and 18q--are also implicated in schizophrenia, as are 2p13 and 10q26, which showed more modest support for linkage. Our results suggest that BP in conjunction with psychosis is a potentially useful phenotype that may: (1) expedite the detection of susceptibility loci for BP and (2) cast light on the genetic relationship between BP and schizophrenia.

Bipolar Disorder↗
PubMed2006

Genetics of suicide.

The concept that genetic factors contribute to the complex trait of suicidal behaviour has stimulated much work aimed at identifying susceptibility genes. So far molecular genetic studies focused on the serotonergic pathway as the intent to die and the lethality of suicide acts were related to the serotonergic system. Two genes have so far emerged as being involved in the vulnerability for suicidality: first, the intronic polymorphisms (A218C or A779C) of the tryptophan hydroxylase 1 (TPH1) gene, which was suggested as a quantitative risk factor for suicidal behaviour; second, the insertion/deletion polymorphism of the serotonin transporter gene (5-HTTLPR), which does not seem to be involved in general suicidal behaviour, but in violent and repeated suicide attempts. The data have further shown that the MAOA gene, which is consistently associated with impulsive-aggressive personality traits, is not related to suicide but might induce violent methods in subjects with other suicide risk factors. Predominantly negative were the findings with any type of the serotonin receptors and inconsistent with catecholamine-synthesizing and -metabolizing enzymes or with the dopaminergic receptors. This paper reviews the status of current knowledge in this area, points to the weakness of the investigations and presents new approaches beyond the serotonergic system.

Brain Chemistry↗
PubMed1999

Gene by environment interaction and asthma.

The term interaction has two specific meanings in epidemiology. The first definition is purely a statistical one. Interaction is defined as the coefficient of the product term of two or more risk factors. An alternative definition is a more biologically oriented one in which interaction between two risk factors is defined as their coparticipation in the same causal mechanism of disease development. There are at least five different types of biological gene by environment interaction. It is important to recognize that clinical or epidemiological studies alone are unable to distinguish between these five different types of biological interaction. Asthma is a prototypical complex trait in which gene by environment interaction is important in disease causation. Environmental factors important in asthma include cigarette smoking (active/passive), allergen exposure, viral and bacterial respiratory illness, occupation, and possibly diet. There are two primary study designs that have been utilized for the assessment of gene by environment interaction: a traditional case control study or a nested case control study or a case control study nested within the larger longitudinal cohort. There are three important methodological issues in the assessment of gene by environment interaction. The first is the issue of misspecification of either genotype or environmental exposure or, for that matter, disease status. The second is possible confounding, and the third is the confounding of interaction with dose response. The four most critical factors for determining sample size for gene by environment interaction studies are the odds ratio for the interaction, the prevalence for exposure in the population, the prevalence of the genotype in the population, and the case to control ratio. In general, sample sizes have been too small to detect meaningful gene by environment interactions.

Animals↗
PubMed2001

Hair on a gene string: recent advances in understanding the molecular genetics of hair loss.

The hair follicle is finally, after remaining a mystery for many years, beginning to yield some of its molecular secrets. The past decade has seen unprecedented and ever quickening advances in understanding the molecular genetics of the many single gene disorders, which have alopecia as a major feature. This article reviews recent novel clinical and experimental observations, which have shed new light on the basic molecular mechanisms underlying hair morphogenesis, differentiation, keratinization and cycling. We consider recent progress in understanding structural hair defects and complex traits and consider where future developments are likely to occur.

Alopecia↗
PubMed2001

The genetic architecture of disease resistance in plants and the maintenance of recombination by parasites.

Parasites represent strong selection on host populations because they are ubiquitous and can drastically reduce host fitness. It has been hypothesized that parasite selection could explain the widespread occurrence of recombination because it is a coevolving force that favours new genetic combinations in the host. A review of deterministic models for the maintenance of recombination reveals that for recombination to be favoured, multiple genes that interact with each other must be under selection. To evaluate whether parasite selection can explain the maintenance of recombination, we review 85 studies that investigated the genetic architecture of plant disease resistance and discuss whether they conform to the requirements that emerge from theoretical models. General characteristics of disease resistance in plants and problems in evaluating resistance experimentally are also discussed. We found strong evidence that disease resistance in plants is determined by multiple loci. Furthermore, in most cases where loci were tested for interactions, epistasis between loci that affect resistance was found. However, we found weak support for the idea that specific allelic combinations determine resistance to different host genotypes and there was little data on whether epistasis between resistance genes is negative or positive. Thus, the current data indicate that it is possible that parasite selection can favour recombination, but more studies in natural populations that specifically address the nature of the interactions between resistance genes are necessary. The data summarized here suggest that disease resistance is a complex trait and that environmental effects and fitness trade-offs should be considered in future models of the coevolutionary dynamics of host and parasites.

Animals↗
PubMed2002

Molecular genecology of temperature response in Lolium perenne: 2. association of AFLP markers with ecogeography.

Improved winter hardiness is an important breeding objective in the forage grass Lolium perenne. This is a complex trait with several components, including the ability to survive and grow at low temperature, to acclimate to cold, tolerate wind, snow cover and ice encasement. Marker-assisted selection has the potential to increase the efficiency of breeding for improved cold tolerance. Here we describe a genecological approach to identifying molecular markers that are associated with adaptation to low winter temperatures. AFLP was used to assess the genetic diversity in 29 wild populations of ryegrass (Lolium perenne) representing a pan-European temperature cline in terms of their geographical origin. A further 18 populations from a temperature cline in Bulgaria were also analysed. In addition, two varieties and five populations representing parents of mapping families currently in use at IGER were included in the analysis. Principal coordinate (PCoA) and cluster analyses of the molecular marker data showed that the Bulgarian altitude cline populations could be distinguished clearly from the other populations. Two regression analyses were carried out; one to identify AFLP markers that correlated in frequency with low mean January temperature of the geographical origin of the population, and another to identify AFLP markers correlating in frequency with the cold tolerance phenotype of the populations, as determined by LT50 values in freezing tests. In the first analysis six AFLP markers showed significant type II trends with mean January temperature, and in the second analysis 28 bands had a significant univariate relationship with the LT50 value of the accessions. In steps 2 and 3 of the stepwise analysis a further 4 and 5 bands, respectively, improved the fit significantly. The results of the two types of regression analysis are discussed in relation to ecogeography and cold tolerance phenotype of the populations.

Ecology↗
PubMed2001

Molecular epidemiology of preterm delivery: methodology and challenges.

Preterm delivery (PTD) appears to be a complex trait determined by both genetic and environmental factors. Few studies have examined genetic influence on PTD. The overall goal of our study is to examine major candidate genes of PTD and to test gene-environment interactions. Our study includes 500 preterm trios, including 500 preterm babies and their parents and 500 maternal age-matched term controls. We will perform the transmission/disequilibrium test (TDT) on candidate genes thought to be important in each of the four biological pathways of PTD: (1) decidual chorioamionotic inflammation: interleukin 1 (IL-1), IL-6, and tumour necrosis factor (TNF); (2) maternal and fetal stress: corticotropin-releasing hormone (CRH); (3) uteroplacental vascular lesions: methylenetereahydrofolate reductase (MTHFR); and (4) susceptibility to environmental toxins: GSTM1, GSTT1, CYP1A1, CYP2D6, CYP2E1, NAT2, NQO1, ALDH2, and EPHX. We will also perform standard case-control analyses on the 500 preterm cases and 500 term controls to examine gene-environment interactions. The major environmental, nutritional and social factors as well as clinical variables known or suspected to be associated with PTD will be used to test for gene-environment interactions. This study integrates epidemiological and clinical data as well as genetic markers along major pathogenic pathways of PTD. The findings from this study should improve our understanding of genetic influences on PTD and gene-environment interactions.

Adult↗
PubMed2003

Fitness-associated recombination on rugged adaptive landscapes.

A negative correlation between fitness and recombination rates seems to exist in various organisms. In this article we suggest that a correlation of that kind may play an important role in the evolution of complex traits. We study the effects of such fitness-associated recombination (FAR) in a simple two-locus deterministic model, as well as in a multi-loci NK rugged adaptive landscape. In both models studied, FAR results in faster adaptation and higher average population fitness, compared with uniform-rate recombination.

Adaptation, Physiological↗
PubMedDate not supplied

Molecular genetics of schizophrenia.

1. Schizophrenia is a chronic, disabling brain disease that affects approximately 1% of the world's population. It is characterized by delusions, hallucinations and formal thought disorder, together with a decline in socio-occupational functioning. While the causes for schizophrenia remain unknown, evidence from family, twin and adoption studies clearly demonstrates that it aggregates in families, with this clustering largely attributable to genetic rather than cultural or environmental factors. Identifying the genes involved, however, has proven to be a difficult task because schizophrenia is a complex trait characterized by an imprecise phenotype, the existence of phenocopies and the presence of low disease penetrance. 2. The current working hypothesis for schizophrenia causation is that multiple genes of small to moderate effect confer compounding risk through interactions with each other and with non-genetic risk factors. The same genes may be commonly involved in conferring risk across populations or they may vary in number and strength between different populations. To search for evidence of such genetic loci, both candidate gene and genome-wide linkage studies have been used in clinical cohorts collected from a variety of populations. Collectively, these works provide some evidence for the involvement of a number of specific genes (e.g. the 5-hydroxytryptamine (5-HT) type 2a receptor (5-HT2a) gene and the dopamine D3 receptor gene) and as yet unidentified factors localized to specific chromosomal regions, including 6p, 6q, 8p, 13q and 22q. These data provide suggestive, but no conclusive, evidence for causative genes. 3. To enable further progress there is a need to: (i) collect fine-grained clinical datasets while searching the schizophrenia phenotype for subgroups or dimensions that may provide a more direct route to causative genes; and (ii) integrate recent refinements in molecular genetic technology, including modern composite marker maps, DNA expression assays and relevant animal models, while using the latest analytical techniques to extract maximum information in order to help distinguish a true result from a false-positive finding.

Animals↗
PubMed2003

Genetic control of susceptibility to bacterial infections in mouse models.

Historically, the laboratory mouse (Mus musculus) has been the experimental model of choice to study pathophysiology of infection with bacterial pathogens, including natural and acquired host defence mechanisms. Inbred mouse strains differ significantly in their degree of susceptibility to infection with various human pathogens such as Mycobacterium, Salmonella, Legionella and many others. Segregation analyses and linkage studies have indicated that some of these differences are under simple genetic control whereas others behave as complex traits. Major advances in genome technologies have greatly facilitated positional cloning of single gene effects. Thus, a number of genes playing a key role in initial susceptibility, progression and outcome of infection have been uncovered and the functional characterization of the encoded proteins has provided new insight into the molecular basis of antimicrobial defences of polymorphonuclear leukocytes, macrophages, as well as T and B lymphocytes. The multigenic control of susceptibility to infection with certain human pathogens is beginning to be characterized by quantitative trait locus mapping in genome wide scans. This review summarizes recent progress on the mapping, cloning and characterization of genes and proteins that affect susceptibility to infection with major intracellular bacterial pathogens.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed1996

Allelic variation of human serotonin transporter gene expression.

Mood, emotion, cognition, and motor functions as well as circadian and neuroendocrine rhythms, including food intake, sleep, and reproductive activity, are modulated by the midbrain raphe serotonin (5-HT) system. By directing the magnitude and duration of postsynaptic responses, carrier-facilitated 5-HT transport into and release from the presynaptic neuron are essential for the fine tuning of serotonergic neurotransmission. Interest in the mechanism of environmental factor-, disease-, and therapy-induced modification of 5-HT transporter (5-HTT) function and its impact on early brain development, event-related synaptic plasticity, and neurodegeneration is widespread and intensifying. We have recently characterized the human and murine 5-HTT genes and performed functional analyses of their 5'-flanking regulatory regions. A tandemly repeated sequence associated with the transcriptional apparatus of the human 5-HTT gene displays a complex secondary structure, represses promoter activity in nonserotonergic neuronal cells, and contains positive regulatory components. We now report a novel polymorphism of this repetitive element and provide evidence for allele-dependent differential 5-HTT promoter activity. Allelic variation in 5-HTT-related functions may play a role in the expression and modulation of complex traits and behavior.

Alleles↗
PubMed2000

An allelic variation in the human prodynorphin gene promoter alters stimulus-induced expression.

Prodynorphin, the precursor of the dynorphin opioid peptides, has been shown to play an important role in several aspects of human diseases and complex traits, e.g., drug abuse, epilepsy, and mood disorders. The objective of this study was to identify polymorphisms in the 5' control region of the human prodynorphin gene and to relate these polymorphisms to prodynorphin gene expression. Within the core promoter region, a 68-bp sequence was found to occur as a polymorphic element, either singular or as tandemly repeated element two, three, or four times. This 68-bp repeat element contains an AP-1 transcription factor binding site as demonstrated by electrophoretic mobility shift assay. Reporter gene assays were performed and provided evidence for allele dependent different promoter activity. Dynorphin was found to be involved in many pathophysiological processes so that the described prodynorphin alleles may correlate with the occurrence of several diseases, for example, drug addiction. However, prodynorphin allelic distributions were not significantly different in heroin addicts and control subjects.

Alleles↗
PubMed2000

Concordance of dermatitis herpetiformis and celiac disease in monozygous twins.

Celiac disease can be defined as the classical manifestation of gluten sensitivity, which primarily affects the small intestine. Gluten sensitivity has also a skin manifestation, i.e., dermatitis herpetiformis. Both diseases have a strong genetic association with HLA DQ on chromosome 6. In this study we tried to estimate how much different clinical expressions of gluten sensitivity are determined by genetic factors, and hence how feasible they are for genetic mapping; therefore, we studied all six monozygous twin pairs found among 1292 prospectively collected patients of dermatitis herpetiformis in Finland. Three of the six twin pairs were concordant for dermatitis herpetiformis and for simultaneous enteropathy, celiac disease. Two other twin pairs were partially discordant, one of each pair had dermatitis herpetiformis and celiac disease, whereas the other had solely the gut manifestation of gluten sensitivity, i.e., celiac disease. Only one pair was found to be discordant for gluten sensitivity. All the pairs had typical risk alleles for gluten sensitivity, i.e., either HLA DQ2 or DQ8. These results demonstrate that the genetic component in gluten sensitivity as broadly defined is very strong (5/6 concordant). Genetically identical individuals can have clearly distinguished phenotypes, either dermatitis herpetiformis or celiac disease, suggesting that environmental factors determine the exact phenotype of this multifactorial disease. These findings are of importance in genetic linkage analyses, which focus to only certain phenotypic properties of a complex trait.

Adult↗
PubMed2004

Exploration of multilocus effects in a highly polymorphic gene, the apolipoprotein (APOB) gene, in relation to plasma apoB levels.

A detailed exploration of all the polymorphisms in candidate genes is required to better characterize the relationship between gene variability and complex traits. We propose a novel strategy for investigating the association between a highly polymorphic gene and a phenotype, by combining a multilocus genotype analysis and an haplotype analysis. For the multilocus genotype analysis, a data mining tool--termed DICE (Detection of Informative Combined Effects)--was developed to identify the best subset of polymorphisms that are associated--individually or in combination--with the phenotype. For the haplotype analysis, we used our recently developed method of haplotype-phenotype association to determine the most informative and parsimonious haplotype model fitting the data. We illustrate this strategy by investigating the association between twelve polymorphisms of the APOB gene and plasma apoB levels in 1442 European subjects. After exploring all main effects and interactions between polymorphisms, DICE identified the N4311S polymorphism as the most informative polymorphism in relation to apoB levels. Haplotype analysis led to the same conclusion. Additionally, DICE identified the E4154K (EcoRI) and the T2488T (XbaI) polymorphisms as potentially interesting. This selection was not modified by inclusion of the common APOE polymorphism in the analysis.

Adult↗
PubMed2003

[Human molecular genetics: from monogenic to polygenic or complex disorders].

Human molecular genetics has successfully identified the genes involved in several monogenic disorders. It now aims at pinpointing the genetic determinants of polygenic or complex traits with a strong genetic component. This constitutes a new challenge. We discuss the methodological and practical aspects of identifying such genes as well as the challenges facing physicians that will have to use efficiently these new diagnostic tools.

Genetic Predisposition to Disease↗
PubMed2003

[Genetics of autism: from genome scans to candidate genes].

The autistic disorder was firstly described by Leo Kanner sixty years ago. This complex developmental disability is characterized by social and communicative impairments and repetitive and stereotyped behaviours and interests. The prevalence of autism in the general population is about 1 in 1,000, with four males affected for one female. In approximately 15% of the cases, autism is associated with known genetic disorders, such as fragile X syndrome, tuberous sclerosis or Rett syndrome. Nevertheless, a recognised medical etiology can only be identified in a minority of cases. A higher recurrence risk in families with autistic subjects (45 times greater than the prevalence in the general population) and higher concordance for autism among monozygotic (60-90%) than dizygotic (0-10%) twins argue for a genetic predisposition to idiopathic autism. The past decade has been marked by an increased interest in the genetic basis of autism, with a series of multiple independent whole genome scans and chromosomal abnormalities studies. These analyses have pointed out several candidate regions on chromosomes 2q, 7q, 6q, 15q and sex chromosomes. These regions possess candidate genes that have been screened for mutations or association with autism. However, a clear involvement of a major susceptibility gene (or genes) in autism remains far from clear. The results from linkage studies and the clear drop in the concordance rates between monozygotic and dizygotic twins suggests that the genetic aetiology of autism is certainly heterogeneous (different genes in different families) and polygenic (more than one affected gene per individual). The almost finished sequence of the human genome and the generation of haplotype maps will shed light on the inter-individual genetic variability and will certainly increase the power and reliability of association studies for complex traits, such as autism.

Autistic Disorder↗
PubMed2005

[WNK1 and WNK4, new players in salt and water homeostasis].

Arterial hypertension is a complex trait influenced by a variety of environmental and genetic factors. Several approaches can be used to identify its susceptibility genes : one is to study rare monogenic forms of hypertension, like familial hyperkalemic hypertension (FHH). Also known as pseudohypoaldosteronism type 2 or Gordon syndrome, FHH is characterized by hypertension, hyperkalemia despite normal renal glomerular filtration rate, abnormalities which are particularly sensitive to thiazide diuretics. Mild hyperchloremia, metabolic acidosis, and suppressed plasma renin activity are associated findings. Despite its phenotypic and genetic heterogeneity, mutations in two related genes, WNK1 and WNK4, were recently identified. These genes belong to a newly identified family of serine-threonine (with no lysine [K]) kinases. Both are highly expressed in the kidney and in a variety of epithelia involved in chloride transport. It has thus been postulated that these two kinases could be implicated in a new pathway of ionic transport regulation. Several studies have very recently confirmed this hypothesis in vitro, in Xenopus oocytes or kidney cell lines. They have shown that, in the renal distal tubule, WNK4 inhibits sodium reabsorption and potassium secretion, via inhibition of NCC (thiazide-sensitive Na+-Cl- cotransporter) and K+ channel ROMK activity, respectively. Interestingly, FHH mutations have opposite effects : while they lead to loss of NCC inhibition, they increase ROMK inhibition. Moreover, they also increase paracellular permeability to chloride of MDCK cells. WNK4 also inhibits apical and basal chloride transporters present in extra-renal epithelia, such as CFEX and Na+-K+-2 Cl-, respectively. It is also interesting to note that the WNK4-mediated negative regulation of NCC activity is in turn inhibited by WNK1. By its role on several transporters, WNK4 appears as a putative key regulator of ionic transport and blood pressure.

Homeostasis↗
PubMedDate not supplied

Assortative mating in the affective disorders: a systematic review and meta-analysis.

Assortative mating, or the tendency for individuals with similar phenotypes to mate more frequently than expected by chance, has been reported for a variety of complex traits, including many neuropsychiatric disorders. Although assortative mating has been reported in affective disorders, the studies done to date have been inconclusive. This study attempts to assess the degree of assortative mating in individuals with affective disorders using systematic review and meta-analytic techniques. Studies on assortative mating in affective disorders were identified by a computerized literature search and by bibliographic assessment of published studies and reviews. Studies were selected if they had a case-control design and if they reported rates of affective disorders in the spouses of probands and controls. Of the 17 studies reviewed, six were selected for meta-analysis. All studies were blinded. Details of study design, patient characteristics, and rates of affective disorders were assessed by two independent reviewers. Twelve of the 17 studies assessed reported an increase in assortative mating. Results of the meta-analysis supported these findings, and indicated that assortative mating occurs in both bipolar disorder and major depression. Although most studies examined reported an increase in assortative mating among individuals with affective disorders, the degree of assortative mating reported varied widely. Meta-analysis with six controlled studies showed evidence for assortative mating, and suggested that the degree of assortative mating is higher for individuals with bipolar disorder than for those with major depression. These results support the previously reported findings, and may have important implications for genetic studies.

Adult↗