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Results for “multifactorial inheritance”

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PubMed2001

Is the genetic liability in multifactorial disorders higher in concordant than discordant monozygotic twin pairs? A population-based family twin study of migraine without aura.

Migraine without aura (MO) is a multifactorial disorder. Expression of a disorder with multifactorial inheritance depends on the genetic liability and on environmental factors. A high liability is reflected by a high frequency of affected relatives. We have previously shown that monozygotic (MZ) twin pairs have a significant higher concordance of MO than dizygotic twin pairs. The incomplete concordance among MZ twin pairs may be due to a lower genetic liability among discordant than concordant MZ twin pairs. The present study analysed the genetic liability in MZ twin pairs concordant and discordant for MO by the population-relative risk of MO among parents and siblings. The twin pairs were from the population-based Danish Twin Register. First-degree relatives of 29 concordant and 34 discordant MZ twin pairs were blindly telephone interviewed by a physician. The participation rate of the eligible first-degree relatives was 96%. The population-relative risk of MO among parents and siblings was 2.73 (2.39-3.06) in concordant and 2.37 (2.03-2.71) in discordant MZ twin pairs. The relative risk of MO was significantly higher in female first-degree relatives of concordant than of discordant MZ male and female twin pairs. An opposite effect was observed in male first-degree relatives, although this was not significant for male first-degree relatives of female MZ twin pairs. The present study found no statistically significant difference in genetic liability to MO among concordant and discordant MZ twin pairs. However, a difference in genetic liability among MZ and DZ twin pairs is anticipated to be small. Thus, it may be possible to show the effect in a larger study population or by investigating a more frequent trait than MO.

Adolescent↗

PubMed2002

Searching for the major histocompatibility complex psoriasis susceptibility gene.

Psoriasis, a common skin disorder, is widely regarded to be multifactorial in origin including gene-gene and gene-environment interactions. Genetic and allelic heterogeneity, multifactorial inheritance, and low penetrance of susceptibility alleles substantially complicate both study design and interpretation of results. Notwithstanding these difficulties, genome-wide scans for psoriasis susceptibility have generated robust evidence for a major locus lying within the major histocompatibility complex (PSORS1, Psoriasis Susceptibility 1), on the short arm of chromosome 6. Subsequent studies have sought to refine the PSORS1 boundaries by means of linkage disequilibrium fine mapping. Studies of positional candidate genes have also been undertaken, focusing on HLA-C, corneodesmosin, and alpha-helix coiled-coil rod homolog genes. Methodologic approaches, results, and interpretations of these studies are discussed, as well as future research objectives. In particular, we emphasize the importance of characterizing PSORS1 linkage disequilibrium patterns and developing functional assays for disease-associated alleles.

Genetic Predisposition to Disease↗

PubMed2001

Genetic susceptibility to macrovascular complications of type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus have a threefold increased risk of developing macrovascular disease such that 75% of such patients will die of cardiovascular complications. This increased risk is, however, not completely explained by traditional risk factors such as smoking, hypercholesterolaemia, hypertension and glycaemic control. Moreover, the fact that not all patients with type 2 diabetes develop these complications, together with evidence of family clustering (a heritability of 50%), suggests that a proportion of the susceptibility to ischaemic heart disease in type 2 diabetes may be genetic. Unravelling the polygenic susceptibility factors for the complications of a disease that itself has multifactorial inheritance has proved difficult and has focused largely on the candidate gene approach. A review of some of the studies testing candidate genes specifically in patients with both type 2 diabetes and ischaemic heart disease is presented. These studies focus largely on four main areas: lipoprotein metabolism, glycation and oxidation pathways, haemostatic cascade, and other candidate genes.

Diabetes Mellitus, Type 2↗

PubMed2006

Genetic factors associated with gout and hyperuricemia.

Hyperuricemia and gout are common conditions that have long been known to have a heritable component. Obesity, diabetes, and chronic kidney failure are conditions with multifactorial inheritance that are associated with gout. In addition, social factors such as protein and alcohol intake affect serum uric acid levels. The current review discusses basic uric acid metabolism and the multigenetic inheritance of hyperuricemia. Several monogenic disorders affecting uric acid metabolism are reviewed. The genetics, pathophysiology, diagnosis, and treatment of familial juvenile hyperuricemic nephropathy/medullary cystic kidney disease, autosomal dominant disorders associated with hyperuricemia and progressive kidney failure, are described.

Blood Group Antigens↗

PubMed2001

Manic depressive psychosis and schizophrenia are neurological disorders at the extremes of CNS maturation and nutritional disorders associated with a deficit in marine fat.

The maturational theory of brain development comprises manic depressive psychosis and schizophrenia. It holds that the disorders are part of human diversity in growth and maturation, which explains their ubiquity, shared susceptibility genes and multifactorial inheritance. Rate of maturation and age at puberty are the genotype; the disorders are localized at the extremes with normality in between. This is based on the association between onset of puberty and the final regressive event, with pruning of 40% of excitatory synapses leaving the inhibitory ones fairly unchanged. This makes excitability, a fundamental property of nervous tissue, a distinguishing factor: the earlier puberty, the greater excitability--the later puberty, the greater deficit. Biological treatment supports deviation from the norm: neuroleptics are convulsant; antidepressives are anti-epiletogenic. There is an association between onset of puberty and body-build: early maturers are pyknic broad-built, late ones linearly leptosomic. This discrepancy is similar to that in the two disorders, supporting the theory that body-build is the phenotype. Standard of living is the environmental factor, which affects pubertal age and shifts the panorama of mental illness accordingly. Unnatural death has increased with antipsychotics. Other treatment is needed. PUFA deficit has been observed in RBC in both disorders and striking improvements with addition of minor amounts of PUFA. This supports that dietary deficit might cause psychotic development and that prevention is possible. Other neurological disorders also profit from PUFA, underlining a general deficit in the diet.

Biological Evolution↗

PubMed2004

Ethical issues in the use of genetic information.

Advances in molecular genetics promise to deepen our understanding of the biological basis of human behavior and shed light on the pathophysiology of mental illness. Genetic research is likely to improve our ability to develop somatic treatments for psychiatric syndromes as well as to identify targets for environmental intervention. However, population-screening tests for disorders with multifactorial inheritance may offer little clinical benefit to outweigh their potential for misuse. Relevant legal issues surrounding the use of genetic information in psychiatry include the perceived need for laws to prevent insurance and employment discrimination, and concerns about genetic status as a possible excuse for criminal behavior. Relevant ethical issues include threats to patient privacy and confidentiality and the importance of fairly distributing the benefits and burdens of genetic advances.

Disclosure↗

PubMed2005

Congenital diaphragmatic hernia and chromosome 15q26: determination of a candidate region by use of fluorescent in situ hybridization and array-based comparative genomic hybridization.

Congenital diaphragmatic hernia (CDH) has an incidence of 1 in 3,000 births and a high mortality rate (33%-58%). Multifactorial inheritance, teratogenic agents, and genetic abnormalities have all been suggested as possible etiologic factors. To define candidate regions for CDH, we analyzed cytogenetic data collected on 200 CDH cases, of which 7% and 5% showed numerical and structural abnormalities, respectively. This study focused on the most frequent structural anomaly found: a deletion on chromosome 15q. We analyzed material from three of our patients and from four previously published patients with CDH and a 15q deletion. By using array-based comparative genomic hybridization and fluorescent in situ hybridization to determine the boundaries of the deletions and by including data from two individuals with terminal 15q deletions but without CDH, we were able to exclude a substantial portion of the telomeric region from the genetic etiology of this disorder. Moreover, one patient with CDH harbored a small interstitial deletion. Together, these findings allowed us to define a minimal deletion region of approximately 5 Mb at chromosome 15q26.1-26.2. The region contains four known genes, of which two--NR2F2 and CHD2--are particularly intriguing gene candidates for CDH.

Abnormalities, Multiple↗

PubMed2006

Linkage of monogenic infantile hypertrophic pyloric stenosis to chromosome 16p12-p13 and evidence for genetic heterogeneity.

Infantile hypertrophic pyloric stenosis (IHPS) is the most common form of bowel obstruction in infancy. The disease affects males four times more often than females and is considered a paradigm for the sex-modified model of multifactorial inheritance. However, pedigrees consistent with autosomal dominant inheritance have also been documented. We analyzed a 3-generation family with IHPS including 10 affected individuals (5 males and 5 females) and mapped the underlying disease locus to chromosome 16p12-p13 (LOD score 3.23) by using a single-nucleotide polymorphism-based genomewide scan. The analysis of 10 additional multiplex pedigrees yielded negative or nonsignificant LOD scores, indicating the presence of locus heterogeneity. Sequence analysis of candidate genes from the chromosome 16 disease interval excluded the presence of pathogenic mutations in the GRIN2A and MYH11 genes.

Chromosome Mapping↗

PubMed1984

The hemi 3 syndrome. Hemihypertrophy, hemihypaesthesia, hemiareflexia and scoliosis.

Three unrelated girls presented with a developmental syndrome of hypertrophy involving half or a quadrant of the body and not involving the face. The appearance was one of inappropriately large size of the affected side rather than contralateral atrophy. On the larger side, there was hypertrophy of muscle and increased power as well as an increase in diameter, but not in length, of long bones. There was areflexia and decreased pain and temperature sensation on that side. The patients also had progressive scoliosis and foot deformities on the enlarged side. One patient had a lumbar myelomeningocoele , and all 3 had a family history of neural tube closure defects. EMG, nerve conduction studies, EEG, skull x-rays, PEG, and cerebral CT scans were normal. Myelography did not demonstrate an enlarged cord, and in particular there was no evidence for syringomyelia. Chromosome studies revealed normal karyotypes. Sex chromatin was female on both sides in one patient. A defect of the dorsal lip of the neural tube or the neural crest is postulated to explain the abnormality. The association with closure defect in one patient and a positive family history of other neural tube defects in all 3 patients suggests that the developmental defect occurs at an early embryonic stage. Recognition of the syndrome is important. It can be distinguished clinically from hemiatrophy of cerebral origin. The neurological abnormalities are static, but the scoliosis is progressive and requires correction. The condition is associated with an increased prevalence of neural tube closure defects in the family, and forms part of a spectrum of genetically and embryologically related CNS malformations with multifactorial inheritance. Probands, parents, siblings and parents' siblings should be counselled that the risks of spina bifida and anencephaly in their offspring are the same as those in relatives of probands with classical neural tube defects, and should be offered prenatal diagnosis.

Adult↗

PubMed1984

Evidence for polygenic epistatic interactions in man?

Studies of multifactorial inheritance in man have ignored nonadditive gene action or attributed it entirely to dominance. Reanalyses of dermatoglyphic data on monozygotic and dizygotic twins, siblings and parents and offspring suggest that a substantial proportion of variation in total finger pattern intensity is due to epistatic interactions between additive genetic deviations, not dominance. Bootstrapping and power simulations support this interpretation of the data. We believe this is the strongest evidence so far for polygenic epistasis in man.

Dermatoglyphics↗

PubMed1998

Positron emission tomography studies of abnormal glucose metabolism in schizophrenia.

Schizophrenia, a devastating disease characterized by a combination of various types of disturbed behaviors, thoughts, and feelings, may likewise be heterogeneous in etiology. Recent advances in neuroscience and psychopharmacology have suggested a wide array of competing mechanisms that may be involved in schizophrenia, including but not limited to deficits in one or more neurotransmitters and second messenger systems (e.g., dopamine, serotonin, gamma-aminobutyric acid, glutamate, and noradrenaline), neurodevelopmental defects in brain circuitry, and viral infection. Psychiatric genetic studies indicate that schizophrenia is a disorder with multifactorial inheritance. Since cerebral metabolic activity reflects regional brain work for all neurotransmitter systems, imaging metabolism directly with fluorodeoxyglucose and indirectly with blood flow and hemoglobin oxygen saturation can provide information about the functional neuroanatomy of a deficit in individual patients and allow patients to be grouped into more homogeneous subgroups for intensive study. This review summarizes metabolic imaging studies in schizophrenia over the past decade.

Antipsychotic Agents↗

PubMed1996

Multiple but different genetic factors underlie enflurane and isoflurane requirements studied through backcross analysis in C57BL and ddN mice.

We performed a classic backcross analysis to examine the basic genetic nature of enflurane (ENF) and isoflurane (ISO) anesthetic requirement in two inbred mice strains, C57BL (BL) and ddN. We have previously reported different ENF and ISO anesthetic requirements in these two strains. BL (n = 22) and ddN (n = 26) mice were used as parents and were reciprocally crossed to produce F1 hybrid mice. Each F1 offspring was crossed to its parent to produce backcross siblings (BF1). Anesthetic end point was determined as the loss of righting reflex. Measurement of anesthetic requirement was performed during 8-12 wk after birth. Although ddN mice showed slightly less resistance to ENF and ISO compared with our previous report, they were more resistant than BL mice. Multivariate regression analysis of parents' and F1 hybrids' data revealed that, while maternal factors and factors on autosomes were related to both anesthetics, the factors on the X chromosome were ENF specific. A wide variation in anesthetic requirements among BF1 progeny suggested multifactorial inheritance. The regression equations obtained did not always predict anesthetic requirement in BF1 progeny. These discrepancies may be due to the epistatic interaction of related genes. We conclude that multiple but different genetic factors are involved in determining ENF and ISO anesthetic requirements in BL and ddN mice.

Anesthetics, Inhalation↗

PubMed1979

Idiopathic scoliosis in identical (monozygotic) twins.

The exact nature of the primary predisposing cause of idiopathic scoliosis is unknown. Hereditary and/or environmental factors may be responsible. Two sets of identical twins presenting in adolescence with concordant scoliotic curves were studied and lend support for a hereditary predisposition favoring a multifactorial inheritance.

Adolescent↗

PubMed2001

The genetics of lupus.

The complex multifactorial inheritance pattern of systemic lupus erythematosus in various murine models has been dissected via both classic genetic analysis and the use of modern technologies in genomic manipulation. Current information suggests that lupus may be mediated by a multitude of genetic abnormalities that impact on specific checkpoints in a three-step pathogenic pathway. These steps are as follows: loss of immunologic tolerance to nuclear antigens; the transition to pathogenic autoimmunity; and end-organ targeting. The identities of the genes that are responsible for transition between the specific steps of the pathway are still unknown and will require further study. However, several recent findings have provided insights into specific elements in each stage of lupus. These findings suggest that mouse models of lupus may provide valuable insights into the genetic basis of human systemic lupus erythematosus.

Gene Expression Regulation↗

PubMed1996

Aetiology and pathogenesis of psoriasis.

The hereditary transmission of psoriasis is suggested by epidemiological data and familial association, but remains incompletely defined, not appearing to follow simple autosomal dominant or recessive patterns. The confusion may be due to a multifactorial inheritance, or to inheritance of only a 'predisposition' to disease which requires an environmental stimuli for expression. Recent advances in genetic mapping indicate genetic heterogeneity, and suggest that definition of psoriasis at the level of the gene may soon be possible. Two of the three major pathogenic features of psoriasis--abnormal keratinocyte differentiation and hyperproliferation of keratinocytes--are secondary to altered growth and maturation kinetics related to the normal wound healing process. The third major pathogenic feature--infiltration of inflammatory components into the skin--can be explained by keratinocyte release of a wide variety of cytokines, immune and inflammatory modulators. Three theories have been proposed for the relationship between epidermal keratinocyte and immunocyte activation. The first theory proposes direct activation of epidermal keratinocytes by physical, chemical, or ultraviolet injury, increasing the synthesis and release of cytokines, which trigger T-lymphocyte activation in an antigen-independent fashion. The other two theories propose persistent T-lymphocyte stimulation as a result of either antigen/superantigen presentation by antigen-presenting cells, or as a result of autoreactivity. One or more of these mechanisms may be operative in different patients, at different times, or in response to different environmental stimuli. Also, the genetic heterogeneity of psoriasis suggests that different mechanisms could be linked to different genetic loci. Advances in understanding the aetiology and pathogenesis of psoriasis suggest the possibility of innovative, targeted therapies.

Adolescent↗

PubMed2004

Mild intellectual disability in children in Lahore, Pakistan: aetiology and risk factors.

BACKGROUND: One of the main objectives of studying intellectual disability (ID) in children is to explore its causes. A specific aetiological diagnosis is important in determining the prognosis, nature and extent of services needed to support affected children. METHODS: Aetiology and risk factors in mild ID were studied in a cohort of longitudinally followed children (6-10 years of age, n = 40) in four population groups in and around Lahore, Pakistan. RESULTS: The overall prevalence of mild ID was 6.2%. In 22% of the cases the onset of mild ID was prenatal with small for gestational age and multifactorial inheritance as the main underlying factors. During the postnatal period (28% of the cases), social deprivation and malnutrition were the major causes of ID. In a substantial proportion of the cases (50%), the cause of ID could not be traced. CONCLUSION: The present study indicates a clear relationship of mild ID with prenatal and postnatal malnutrition and social deprivation. Two independent variables, maternal illiteracy and small head circumference at birth, showed a clear association with the development of mild mental disability among children in the study population.

Catchment Area, Health↗

PubMed1979

Familial congenital diaphragmatic hernia: prenatal diagnostic approach and analysis of twelve families.

Congenital diaphragmatic hernia is generally recognized as a sporadic malformation with little or no risk of recurrence. A family with three affected individuals in two generations is presented. In addition, new prenatal diagnostic techniques including ultrasonography and amniography are discussed. A comparison of associated physical characteristics in isolated versus twelve familial cases of diaphragmatic hernia is presented. In the familial group, there was a higher incidence of affected males (M:F ratio = 2.1 versus 0.67), a higher incidence of bilateral defects (20% versus 3%) and a lower incidence of additional life-threatening malforamtions 3.6% versus 47%). Analysis of available pedigree data favors multifactorial inheritance with a high male: female sex ratio as the most probable mode of transmission.

Abnormalities, Multiple↗

PubMed1980

Familial Williams syndrome.

Characteristic features of the Williams syndrome were observed in a mother and her presumably dizygotic twin daughters, suggesting either an X-linked dominant, autosomal dominant or multifactorial inheritance in this pedigree. The Williams syndrome generally has been thought to have a sporadic occurrence. The rare familial occurrence, however, suggests a possible heterogeneity in its etiology and also points out the importance of careful examination of the other family members for proper genetic counseling.

Abnormalities, Multiple↗