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Results for “complex trait”

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At least 937 records · Page 52Linked to original sources
PubMed2003

Interaction effect of Serine447Stop variant of the lipoprotein lipase gene and C-514T variant of the hepatic lipase gene on serum triglyceride levels in young adults: the Bogalusa Heart Study.

The opposing effects of lipoprotein lipase (LPL) Serin447Stop (S447X) polymorphism and hepatic lipase (HL) C-514T polymorphism on serum triglyceride (TG) levels have been known. However, little is known about the interaction effect of these 2 functional gene variants on serum triglyceride levels. This aspect was examined in a community-based sample of 902 whites and 389 blacks aged 18 to 41 years, using a repeated measures analysis in a mixed model. The frequency of the LPL X447 allele was higher in whites than blacks (16% v 11%, P <.05); whereas the frequency of HL T-514 allele was higher in blacks than whites (77% v 40%, P <.001). The combined genotype distribution was also different between whites and blacks (P <.001). Although the frequency of carriers of both variants was similar in whites and blacks (7% v 8%), more whites carried the LPL X447 allele only (9% v 3%), and more blacks carried the HL T-514 allele only (70% v 33%). Mean levels of TG adjusted for age, sex, and body mass index (BMI) in carriers versus noncarriers of the LPL X447 allele were lower by 13.5% (P <.0001) in whites, 15.8% (P <.01) in blacks and 16.0% (P <.0001) in the total sample. No such phenotypic effect was noted with respect to HL T-514 allele either in blacks or whites, although the mean level in carriers was marginally (P =.08) higher in the total sample. The interaction effect of LPL and HL variants on TG levels was significant in the total sample (P =.016) and marginal in whites (P =.079). In the total sample, the decrease of TG in carriers versus noncarriers of the LPL X447 was 1.8-fold greater in carriers versus noncarriers of the HL T-514 allele (13.6 mg/dL v 7.4 mg/dL, P =.016). Whites tended to show a similar trend (16.8 mg/dL v 6.1 mg/dL, P =.079). Blacks also showed a similar, but nonsignificant, trend (10.4 mg/dL v 8.6 mg/dL, P =.45). These results by showing modulation of association between S447X variant of the LPL gene and serum TG by C-514T variant of the HL gene underscore the importance of gene-gene interactions in the assessment of genetic effects on complex traits.

Adult↗
PubMed2001

Linkage and association with structural relationships.

The use of structural equations (path analysis) provides an alternative, equivalent formulation to variance components models. Instead of partitioning the variance, we focus on modeling the underlying random variables themselves through a system of linear, mixed model, regression equations. A few specific examples of genetic path models for linkage and association (linkage disequilibrium) are discussed. This formulation provides a simple yet elegant framework that can continue to be extended to meet the challenges of modeling and dissecting the genetic nature of complex traits in the new century.

Chromosome Mapping↗
PubMed2000

Syndromes associated with Homo sapiens pol II regulatory genes.

The molecular basis of human characteristics is an intriguing but an unresolved problem. Human characteristics cover a broad spectrum, from the obvious to the abstract. Obvious characteristics may include morphological features such as height, shape, and facial form. Abstract characteristics may be hidden in processes that are controlled by hormones and the human brain. In this review we examine exaggerated characteristics presented as syndromes. Specifically, we focus on human genes that encode transcription factors to examine morphological, immunological, and hormonal anomalies that result from deletion, insertion, or mutation of genes that regulate transcription by RNA polymerase II (the Pol II genes). A close analysis of abnormal phenotypes can give clues into how sequence variations in regulatory genes and changes in transcriptional control may give rise to characteristics defined as complex traits.

Amino Acid Sequence↗
PubMed2002

Multiple sclerosis.

Multiple sclerosis is the prototype inflammatory autoimmune disorder of the central nervous system and, with a lifetime risk of one in 400, potentially the most common cause of neurological disability in young adults. As with all complex traits, the disorder results from an interplay between as yet unidentified environmental factors and susceptibility genes. Together, these factors trigger a cascade of events, involving engagement of the immune system, acute inflammatory injury of axons and glia, recovery of function and structural repair, post-inflammatory gliosis, and neurodegeneration. The sequential involvement of these processes underlies the clinical course characterised by episodes with recovery, episodes leaving persistent deficits, and secondary progression. The aim of treatment is to reduce the frequency, and limit the lasting effects, of relapses, relieve symptoms, prevent disability arising from disease progression, and promote tissue repair. Despite limited success in each of these categories, everyone touched by multiple sclerosis looks for a better dividend from applying an improved understanding of the pathogenesis to clinical management.

Adult↗
PubMed2003

Problems of reporting genetic associations with complex outcomes.

Inability to replicate many results has led to increasing scepticism about the value of simple association study designs for detection of genetic variants contributing to common complex traits. Much attention has been drawn to the problems that might, in theory, bedevil this approach, including confounding from population structure, misclassification of outcome, and allelic heterogeneity. Other researchers have argued that absence of replication may indicate true heterogeneity in gene-disease associations. We suggest that the most important factors underlying inability to replicate these associations are publication bias, failure to attribute results to chance, and inadequate sample sizes, problems that are all rectifiable. Without changes to present practice, we risk wastage of scientific effort and rejection of a potentially useful research strategy.

Alleles↗
PubMed2003

Twinning.

Twinning has fascinated human beings over the centuries. New technologies and large study groups have led to improved documentation of frequency and complications in twin pregnancies and long-term outcomes. Artificial reproductive technologies have led to a pronounced rise in numbers of dizygotic and monozygotic twins. Although spontaneous dizygotic twinning is clearly associated with increased concentration of follicle-stimulating hormone and ovulation of more than one egg, causes of monozygotic twinning remain illusive. Twin studies are used increasingly to study complex traits and disorders: however, caution is suggested, since twins might not be representative of a typical singleton pregnancy. Monozygotic twinning seems to represent an anomaly in itself, with an increased number of spontaneous abortions and structural congenital anomalies. Both monozygotic and dizygotic twins have growth rates that slow at 30 weeks in utero and might be programmed both developmentally and biochemically earlier in pregnancy to have different responses at birth and after birth compared with singletons.

Chorion↗
PubMed2004

Parent-of-origin effect in multiple sclerosis: observations in half-siblings.

Multiple sclerosis is a complex trait in which occurrence rates in offspring are 20-50-fold greater than in the general population. Parent-of-origin effects have been difficult to screen for, since most cases are sporadic. We have compared recurrence risks in half-siblings with respect to their parent in common. Of the 1567 index cases with half-siblings in multiple sclerosis clinics across Canada, we recorded 3436 half-siblings and 2706 full-siblings. Age-adjusted full-sibling risk was 3.11%. By contrast, half-sibling risk in the same families was significantly lower at 1.89% (chi2 test, p=0.006), but higher than expected if familial risk was simply polygenic. For maternal half-siblings, the risk was 2.35% (34 affected siblings of 1859), and 1.31% for paternal half-siblings (15 of 1577), (p=0.048). The difference in risk suggests a maternal parent-of-origin effect in multiple sclerosis susceptibility.

Female↗
PubMed2006

Adult epilepsy.

The epilepsies are one of the most common serious brain disorders, can occur at all ages, and have many possible presentations and causes. Although incidence in childhood has fallen over the past three decades in developed countries, this reduction is matched by an increase in elderly people. Monogenic Mendelian epilepsies are rare. A clinical syndrome often has multiple possible genetic causes, and conversely, different mutations in one gene can lead to various epileptic syndromes. Most common epilepsies, however, are probably complex traits with environmental effects acting on inherited susceptibility, mediated by common variation in particular genes. Diagnosis of epilepsy remains clinical, and neurophysiological investigations assist with diagnosis of the syndrome. Brain imaging is making great progress in identifying the structural and functional causes and consequences of the epilepsies. Current antiepileptic drugs suppress seizures without influencing the underlying tendency to generate seizures, and are effective in 60-70% of individuals. Pharmacogenetic studies hold the promise of being able to better individualise treatment for each patient, with maximum possibility of benefit and minimum risk of adverse effects. For people with refractory focal epilepsy, neurosurgical resection offers the possibility of a life-changing cure. Potential new treatments include precise prediction of seizures and focal therapy with drug delivery, neural stimulation, and biological grafts.

Adult↗
PubMed1997

Offspring recurrence rates and clinical characteristics of conjugal multiple sclerosis.

BACKGROUND: There has been no previous systematic study of conjugal multiple sclerosis. This study of conjugal pairs with complex traits investigated disease transmissibility and the genetic contribution to frequency and clinical course. METHODS: We studied 45 conjugal pairs concordant for multiple sclerosis from 58 pairs recorded in a national register of familial disease, 86 offspring of the 45 pairs were individually assessed for clinical evidence of neurological disease; those over age 16 underwent cranial magnetic resonance imaging. Clinical features were compared in 33 pairs in whom neither member had symptoms before they met. FINDINGS: Of the 86 offspring, five (6%) had clinically definite multiple sclerosis. A further five children had either characteristic imaging abnormalities or clinical symptoms consistent with demyelination, but did not meet the criteria for clinically definite disease. There was no evidence of clinical concordance, clustering at year of onset, or distortion of the expected pattern of age of onset in the second affected spouse from 33 pairs. The crude recurrence in children of conjugal pairs (1 in 17) is significantly higher than previously reported population-based risk for offspring of single affected parents (1 in 200). INTERPRETATION: Taken with the low prevalence of multiple sclerosis in the spouses of affected individuals, and the lack of concordance for age at onset in these families, the disparity in crude recurrence between children of conjugal pairs and those of single affected parents shows that the recurrence risk in children is determined by genetic factors inherited from both parents.

Adolescent↗
PubMed1998

HLA associations with multiple sclerosis in the Canary Islands.

The study of small island populations has proved informative with respect to the epidemiology and genetics of many complex traits including multiple sclerosis. The class II major histocompatibility antigen DR15 is associated with multiple sclerosis in all groups except Sardinians, where the primary association is with DR4. We compared HLA-DR and -DQ allele frequencies in a representative sample of patients with multiple sclerosis from the Canary Islands with appropriate controls. There was a significant association with DR15 (patients 21/53: 40%: controls 11/55; 20%: chi2=4.09; pc=0.04; relative risk [RR]=1.98). DRB1*1501-DRB5*0101 was present in 17/53 (32%) patients in whom sub-types could be identified compared with 6/55 (11%) controls (chi2=7.21; pc=< 0.01; RR=2.94). All DR15 positive controls carried the DQA1*0102, DQB1*0602 haplotype whereas this was only present in 26/30 patients, suggesting that the primary association is with HLA-DR and not -DQ. We also found a significant increase in HLA-DR4 (16/53 [30%] in patients compared with 7/55 [13%] in controls; pc=0.05). This study contributes a new point on the immunogenetic map of multiple sclerosis in Europe, confirming the primary DR15 association with multiple sclerosis in a previously unstudied population but again highlighting the importance of DR4 in Mediterranean peoples.

Alleles↗
PubMed2003

Using genome-wide mapping in the mouse to identify genes that influence drug response.

Differential drug response is most often likely to be a complex trait, controlled by the combined influences of multiple genes and environmental influences. As a result of theoretical and technical limitations, to date, most clinically useful pharmacogenomic studies in humans have been limited to a small number of candidate genes that have a relatively major impact on drug response. Here, the problems involved in identifying genes that underlie drug response in humans are discussed and the power of mouse genetics as a tool for pharmacogenomic discovery is highlighted.

Animals↗
PubMed2002

Does variability in normal tissue reactions after radiotherapy have a genetic basis--where and how to look for it?

Cancer patients exhibit large patient-to-patient variability in normal tissue reactions after radiotherapy. Several observations support the hypothesis that clinical normal tissue radiosensitivity is influenced by genetic factors. However, very little is known about the genetic variation possibly underlying inter-individual differences in normal tissue reactions when unselected cancer patients undergo radiotherapy. It seems reasonable to assume that clinical radiosensitivity of normal tissues should be regarded as a so-called complex trait depending on the combined effect of several different genetic alterations. Single nucleotide polymorphisms (SNPs) make up 90% of naturally occurring sequence variation in the human genome and SNPs in genes related to the biological response to ionising radiation may affect clinical radiosensitivity. Rare genetic variants could also possibly play an important role. Thus, the 'allelic architecture' underlying differences in normal tissue reactions may be rather complicated. Recent advances in high throughput genotyping and bio-informatics provide unprecedented opportunities to unravel the genetic basis of clinical normal tissue radiosensitivity. However, to achieve maximum benefit from these advances, carefully designed clinical studies with an accrual of hundreds or thousands of patients are probably needed.

Cell Survival↗
PubMed2003

Wild mice: an ever-increasing contribution to a popular mammalian model.

Classical laboratory inbred strains of mice have been extremely helpful for research in immunology and oncology, and more generally, for the analysis of complex traits. Unfortunately, because they all derive from a relatively small pool of ancestors, their genetic polymorphism is rather limited. However, recently strains belonging to different species of Mus have been established from wild progenitors. These are an interesting addition to the arsenal of mouse geneticists, because they can be crossed with classical laboratory strains to produce viable and fertile offspring with a large number of polymorphisms of natural origin. These strains are helpful for making genome annotations because they permit highly refined genotype-phenotype correlations. They also allow the interpretation of molecular variation within a clear evolutionary framework. In this article, we provide examples with the aim of promoting the use of these new strains.

Animals↗
PubMed2001

Lack of linkage and association between autoimmune thyroid diseases and the CTLA-4 gene in a large Tunisian family.

The autoimmune thyroid diseases (AITDs) including Graves' disease and Hashimoto's thyroiditis are inherited as complex traits. We have performed linkage and association studies to investigate the role of CTLA-4 gene in the AITDs development using the D2S311, D2S143, the intragenic CTLA-4 (AT)(n) microsatellite markers and the CTLA-4 (A/G) dimorphism in exon 1. Four extended pedigrees belonging to a large Tunisian family named Akr and including 154 individuals from which 20 were affected with Hashimoto's thyroiditis and 26 with Graves' disease, were used in this investigation. No evidence for linkage with none of the markers was found under neither dominant nor recessive models [Z=-7.14 and Z=-14.32 at theta=0.0, respectively for the CTLA-4 (AT)(n) marker]. A family-based association study on 51 nuclear families derived from the Akr pedigree was performed by the FBAT approach applied to the CTLA-4 (AT)(n) marker and the CTLA-4 (A/G) dimorphism. We found no association of individual alleles to disease for both markers. These results showed no evidence for the involvement of the CTLA-4 locus in the AITDs pathogenesis.

Abatacept↗
PubMed1999

The genetics of endometriosis.

There is mounting evidence that endometriosis is inherited as a complex trait, like diabetes or asthma. This implies there are environmental factors, such as dioxin, that are interacting with multiple genetic susceptibility loci to produce the phenotype. The Oxford Endometriosis Gene (OXEGENE) study, an international collaborative project, seeks to identify the susceptibility loci using linkage analysis; the aim then is to use positional cloning techniques to identify genes that predispose women to the disease. Analysis of the biochemical function of the gene products will lead to a better understanding of the pathophysiology and aetiology of endometriosis. New therapies may be designed based upon knowledge of the gene function and disease associated genetic markers may be used to identify women at high risk of developing the disease.

Animals↗
PubMed1998

Genetics of polycystic ovary syndrome.

We have found evidence for the involvement of two major genes in the aetiology of PCOS. The results of both linkage and association studies suggest that CYP11a (coding for P450 cholesterol side chain cleavage) and the insulin VNTR regulatory polymorphism are important genes in the aetiology of PCOS and may explain, in part, the heterogeneity of the syndrome. Differences in expression of CYP11a could account for variation in androgen production in women who have polycystic ovaries and those subjects who are homozygous for III alleles at the insulin gene VNTR locus are more likely to be hyperinsulinaemic. It is likely that other genes are involved in the aetiology of PCOS. Recent results lend weight to the idea that PCOS represents a complex trait in which several genes--but perhaps a relatively small number of key genes--contribute, in conjunction with nutritional factors, to the observed clinical and biochemical heterogeneity.

Androgens↗
PubMed2002

The tau H1 haplotype is associated with Parkinson's disease in the Norwegian population.

We investigated the association of Parkinson's disease (PD) with tau gene H1 haplotypes in the Norwegian population. In a sample of 96 unrelated PD cases and 68 control subjects, we observed an increased risk of PD for persons with the tau H1 haplotype (odds ratio=5.52; 95% confidence interval: 2.64-11.10; P=2.17x10(-6)). Findings provide evidence that tau participates in the PD pathogenic process and demonstrate the value of isolated populations in mapping complex traits.

Adult↗
PubMed2001

Construction of a physical map of an autism susceptibility region in 7q32.3-q33.

The fast evolving progress of the human genome mapping and sequencing efforts facilitate the detection of genes also for complex traits. We focus on the detection of susceptibility loci for autism, a prototypical pervasive developmental disorder. Five genome screens worldwide have identified several putative locations of susceptibility genes thus far, with the most common region on chromosome 7q. In order to identify new candidate genes for infantile autism we constructed a physical map of bacterial artificial chromosome, P1-derived artificial chromosome and yeast artificial chromosome clones of a 3 Mb region between D7S1575 and D7S500, including a complete contig of the approximately 1.2 Mb region around D7S2533, the marker with the most significant association result. We developed 16 novel sequence tag sites and mapped 23 genes/expressed sequence tags to the contigs. As this map contains a putative autistic disorder locus this integrated physical and transcript map provides a valuable resource for identification of candidate gene(s).

Autistic Disorder↗