Relative Contribution Of Genetic Factors Research Articles

Differentially expressed genes in an animal model of psychosis associated to schizophrenia within a large case-control study

There is evidence for a strong genetic component in the aetiology of schizophrenia, as demonstrated by family, twin and adoption studies. The relative contribution of genetic factors has been estimated to be up to 80%. The mode of inheritance is complex, involving the combined action of several genes, each of which might account for only a small part in the susceptibility. Several complementary strategies are needed to approach the pathobiology and genetics of schizophrenia including genetic association studies as well as animal and cell culture models. We first aimed to identify further schizophrenia genes in a large case-control study. 700 patients with schizophrenia and 200 first degree relatives were included as well as 2000 community-based healthy volunteers. More than 1000 SNPs covering app.170 candidate genes were genotyped. Furthermore, we used an NMDA receptor antagonist animal model which mimics several aspects of psychosis to identify further candidate genes which can be used in our human studies. In our model, chronic, low-dose treatment with MK801 alters the expression of NMDA receptor subunits in a pattern similar to schizophrenia on the molecular level. We used a functional genomic approach for the identification of candidate genes for psychosis-related traits and identified several differentially expressed genes in the rat hippocampus. These genes have been genotyped in our large case-control study and results of these associations will be presented.

Influence of genetics on irritable bowel syndrome, gastro‐oesophageal reflux and dyspepsia: a twin study

A genetic contribution has been proposed for irritable bowel syndrome (IBS) and gastro-oesophageal reflux disease (GERD), but is controversial. No twin data exist for dyspepsia. To determine the relative contribution of genetic factors in GERD, dyspepsia (upper abdominal pain) and IBS. A total of 986 twin pairs (from initial mail-out response 51%). Both members completed validated symptom and psychological questionnaires; 481 monozygotic pairs [mean (s.d.) age 53 +/- 5.8 years] and 505 dizygotic pairs (mean age 54 +/- 5.6 years). Prevalence of IBS, dyspepsia and GERD was 12%, 10% and 20%, respectively. Polychoric correlation for monozygotic twins for IBS (0.47) and GERD (0.44) were both substantially larger than those for dizygotic twins (0.17 and -0.37, respectively). Polychoric correlation was slightly lower in monozygotic than dizygotic twins for dyspepsia. Genetic modelling confirmed the independent additive genetic effects in GERD and IBS but not dyspepsia. Estimates of genetic variance were 22% for IBS, 13% for GERD and 0% for dyspepsia, but adjusting for anxiety and depression removed the statistical significance for IBS and GERD. There is a genetic contribution to GERD and IBS but not dyspepsia; this may be mediated by the hereditability of anxiety and depression.

Asthma phenotypes

Asthma is a heterogeneous disorder presenting with many phenotypes. Precise phenotypic definition has eluded the medical research community for years, despite recognition of different disease subtypes. Improved phenotypic characterization and knowledge of underlying pathobiology is necessary for linkage of specific genotypes with clinical disease manifestations. Phenotyping has been difficult because asthma is likely to be comprised of overlapping syndromes with varying origins and heterogeneous pathobiology. Currently, the field is too reliant on classification by trigger or symptoms. Since genotypic and phenotypic heterogeneity are inherent in asthma, patients presenting with different asthma phenotypes may need tailored therapies. Studies have begun to link genetics with disease mechanism and therapeutic response. As disease etiology, onset, progression and severity vary greatly among patients, however, the relative contribution of genetic factors may be difficult to ascertain. Definition of the full array of complex biological consequences of molecular target modulation is a prerequisite for therapies based on this concept. The advent of targeted therapies for asthma and clinical trials based on phenotype and genotype have raised interest in more accurate description of asthma phenotypes. Therapies based on phenotypic and genotypic characteristics may be useful in asthma management. A variety of factors, however, must be addressed before such approaches become standard.

Genes encoding for AP-2β and the Serotonin Transporter are associated with the Personality Character Spiritual Acceptance

In several twin studies the relative contribution of genetic factors for personality traits has amounted to figures between 40 and 60%. In the present study we investigated to which degree polymorphisms in the 5-HTT and AP-2β genes are implicated in the neural processes involved in the formation of Temperament and Character traits, as estimated by Cloninger's TCI. Considering the background of previous reports, associations with the character Self-Transcendence and its sub-scale Spiritual Acceptance in particular, were of interest. A stratified random sample of 200 individuals (total population = 5173), matched for age, gender and risk behaviors, from volunteering 16- and 19-year-old adolescents students in Sweden was investigated. Cloninger's TCI inventory was used for investigation of temperament and character traits. Blood samples were used for analyses of a promoter serotonin transporter polymorphism (5-HTTLPR) and an intron 2 polymorphism in the transcription factor AP-2β gene. Among boys individuals with presence of the short 5-HTTLPR genotype showed lower scores, whereas individuals with presence of the short AP-2β genotype showed higher scores of personality character Self-Transcendence and its sub-scale Spiritual Acceptance. Among girls no effect of either genotype was found. Both among boys and girls, significant interactive effects were found between 5-HTTLPR and AP-2β genotypes, with regard to Self-Transcendence and Spiritual acceptance. Boys and girls with the combination of presence of the short 5-HTTLPR, and homozygosity for the long AP-2β genotype scored significantly lower on Self-Transcendence and Spiritual Acceptance.

Relative Contribution of Genetic and Nongenetic Modifiers to Intestinal Obstruction in Cystic Fibrosis

Neonatal intestinal obstruction (meconium ileus [MI]) occurs in 15% of patients with cystic fibrosis (CF). Our aim was to determine the relative contribution of genetic and nongenetic modifiers to the development of this major complication of CF. A total of 65 monozygous twin pairs, 23 dizygous twin/triplet sets, and 349 sets of siblings with CF were analyzed for MI status, significant covariates, and genome-wide linkage. Specific mutations in the CF transmembrane conductance regulator (CFTR), the gene responsible for CF, correlated with MI, indicating a role for CFTR genotype. Monozygous twins showed substantially greater concordance for MI than dizygous twins and siblings (P = 1 x 10(-5)), showing that modifier genes independent of CFTR contribute substantially to this trait. Regression analysis revealed that MI was correlated with distal intestinal obstruction syndrome (P = 8 x 10(-4)). Unlike MI, concordance analysis indicated that the risk for development of distal intestinal obstruction syndrome in CF patients is caused primarily by nongenetic factors. Regions of suggestive linkage (logarithm of the odds of linkage >2.0) for modifier genes that cause MI (chromosomes 4q35.1, 8p23.1, and 11q25) or protect from MI (chromosomes 20p11.22 and 21q22.3) were identified by genome-wide analyses. These analyses did not support the existence of a major modifier gene on chromosome 19 in a region previously linked to MI. The CFTR gene along with 2 or more modifier genes are the major determinants of intestinal obstruction in newborn CF patients, whereas intestinal obstruction in older CF patients is caused primarily by nongenetic factors.

GENETIC EPIDEMIOLOGY OF CANNABIS USE, ABUSE AND DEPENDENCE: A COMMENT ON AGRAWAL & LYNSKEY (2006)

Agrawal & Lynskey [1] have written a comprehensive and thoughtful review of the current state of knowledge in this area. First, they review studies demonstrating a wide range of estimates for the relative contribution of genetic factors, i.e. heritability, to the interindividual variation in cannabis use, abuse and dependence, with a heavy emphasis on twin studies. Through twin studies they also explore the nature of the relationship of cannabis use with licit (tobacco and alcohol) and illicit drug use, and show that there are probably underlying genetic mechanisms and dispositions in common. They conclude by reviewing avenues for future research that have not yet been explored to any great degree. These include broadening the phenotype to include other aspects of cannabis use/abuse, and its potential endophenotypes [2]. In addition to those mentioned by the review, neurophysiological, neuroimaging and neuropsychological-based endophenotypes should be explored in genetically informative designs. These have proved very useful in other substance use research and in schizophrenia research [3, 4]. As cannabis use is a risk factor for schizophrenia and psychosis [5, 6], understanding the aetiology and pathology of cannabis addiction might also help us understand psychoses and schizophrenia better. A limitation of current studies on the genetic epidemiology of cannabis addiction is their very restricted provenance, as acknowledged in the review. Virtually all have been conducted in Anglo-Saxon societies, despite which a very wide range of heritability estimates has been derived, and virtually all studies indicate a major role for shared environmental effects in addition to genetic effects. Studies from other cultures with different experiences of cannabis use are needed. We have assessed cannabis use as part of our ongoing longitudinal studies of adolescent twins in Finland. In the FinnTwin 12 study of Finnish adolescent twins born in 1983–87, more than a third of subjects reported alcohol use when surveyed by questionnaire immediately after their 14th birthday [7]. Among 1854 of the same twins interviewed at age 14 years, only 1.1% had experimented (at least once) with cannabis and no genetic modelling was possible. The third wave of the same study was carried out in 2000–05, when the twins were aged 17 years [8]. Among 1905 monozygotic (MZ) and dizygotic (DZ) pairs, > 13% reported experimentation and 1.6% had used 20 or more times in a mailed questionnaire survey. Pairwise tetrachoric correlations for any use were high in male (0.89) and female (0.87) MZ pairs, while correlations were somewhat lower in male DZ pairs (0.71), female DZ pairs (0.70) and male–female DZ pairs (0.52). In the FinnTwin16 study of Finnish twins born from 1975 to 1979, cannabis and other illicit drug use was asked of them as young adults [8] at an average age of 24 years during 2000–02. More than 22% reported experimentation and 3.7% had used 20 or more times. Among the surveyed twins (n = 2005 MZ and DZ pairs), tetrachoric correlations for any use were high in male and female MZ pairs (both r = 0.81), while correlations were lower in male DZ pairs (0.64), female DZ pairs (0.49) and male–female DZ pairs (0.33). Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA)-based [9] interviews of a subset of subjects (n = 602 twins) indicated a high reliability of the history of any use of cannabis (kappa = 0.85) from the questionnaire. The pattern of correlations in the two Finnish studies indicates the presence of substantial genetic effects and shared environmental effects even without carrying out formal genetic modelling in this non-Anglo-Saxon population in which cannabis use is less frequent than in the reviewed studies. In many aspects, the genetic epidemiology of cannabis resembles that of alcohol use, for which substantial shared environmental effects have also been demonstrated and for which gene–environment interaction effects are recognized [10]. The heritability of adolescent alcohol use ranges widely in different social contexts [11-13] even within Finland, which is a relatively homogeneous country genetically and culturally. It is likely that gene–environment interaction accounts for a substantial proportion of the apparent heritability of cannabis use and abuse. This would suggest that the relative importance of direct versus indirect genetic influences on cannabis use should be explored carefully before embarking on expensive molecular genetic studies.

The inheritance of susceptibility to lichen planus

The role of inheritance of susceptibility in lichen planus was studied by genetic analysis of data from 71 families of probands with lichen planus. 12 families were multiplex and the other 59 were simplex. The incidence of the disease among relatives of probands was significantly higher than that in the general population and the frequency diminished with the descend in the degree of relationship between relatives and probands. Pedigrees of the families of probands did not consist of any single-gene inheritance. The results shown by the curve of liability of the relatives, the frequency in the first degree relatives and the relative frequency points to a polygenic-environmental interaction. The heritability of liability for lichen planus which measures the relative contribution of genetic factors in etiology was found to be 56 percent for first-degree relatives. The etiology of lichen planus is still not properly known. Several pathogenetic theories have been proposed despite limited supportive evidences. The main theories are: infective, autoimmune, psychogenic and genetic. The aim of this work is to throw a beam of light on the genetic role in the pathogenesis of lichen planus.

Clozapine-induced weight gain: a study in monozygotic twins and same-sex sib pairs

To assess the relative contribution of genetic factors in antipsychotic-induced weight gain, we explored the similarity in body mass index (BMI) (kg/m(2)) change under clozapine only (clozapine DeltaBMI) and upon additional inclusion of BMI change under prior antipsychotic medication (total DeltaBMI) of five monozygotic twins in comparison with seven same-sex sibs. Twin and sib pairs were identified by a telephone screening of 786 office-based psychiatrists. Measured data on weight and other clinical variables were obtained cross-sectionally and retrospectively from medical records. We found greater similarity in total DeltaBMI in monozygotic twins (intrapair difference 2.78+/-3.41 kg/m(2)) than in same-sex sibs (5.55+/-4.35 kg/m(2)), resulting in heritability estimates of h(2)=0.8 and A=0.45 (ACE twin model). However, intrapair differences in clozapine DeltaBMI were similar between twins (4.18+/-4.27 kg/m(2)) and sibs (4.68+/-4.88 kg/m(2)). We hypothesize that the weight plateau achieved under clozapine is influenced by genetic factors. The weight gain achieved during pretreatment with other antipsychotics seems to limit clozapine-induced weight gain, thus presumably explaining why heritability/similarity in monozygotic twins in comparison with same-sex sibs is greater for total DeltaBMI than for clozapine DeltaBMI. An important caveat is that, owing to the sample size, the heritability estimates have a large standard error and thus have to be interpreted with caution.

Quantitative ultrasound of the hand phalanges in a cohort of monozygotic twins: influence of genetic and environmental factors

Our objective was to evaluate the similarities and differences in bone mass and structure between pairs of monozygotic twins as measured by means of the quantitative ultrasound (QUS) technique. A cohort of monozygotic twins was measured by QUS of the hand phalanges using the DBM sonic bone profiler (IGEA, Carpi, Italy). The parameters studied were amplitude-dependent speed of sound (AD-SoS), ultrasound bone profile index (UBPI), signal dynamics (SDy) and bone transmission time (BTT). Linear correlation coefficients, multivariate linear analysis and the ANOVA test were used to assess intrapair associations between variables and to determine which factors influence the intrapair differences in QUS variables. One hundred and six pairs of monozygotic twins were enrolled in the study, 68 females and 38 males in the age range 5 to 71 years. Significant intrapair correlations were obtained in the whole population and separately for males and females, regarding height ( r =0.98-0.99, p <0.0001), weight ( r =0.95-0.96, p <0.0001), AD-SoS ( r =0.90-0.92, p <0.0001), BTT ( r =0.94-0.95, p <0.0001) and other QUS parameters ( r >0.74, p <0.0001). Multivariate analysis revealed that intrapair differences between AD-SoS, SDy, UBPI and BTT are significantly influenced by age in the whole population and in the female population. Furthermore, the ANOVA test showed, for the female group, a significant increase in the intrapair differences in SDy and UBPI above 40 years. A relative contribution of genetic factors to skeletal status could be observed by phalangeal QUS measurement in monozygotic twins. A significant increase in the intrapair difference in QUS parameters with increasing age and onset of menopause also suggests the importance of environmental factors in the female twin population.

Genetic Influences in Irritable Bowel Syndrome: A Twin Study

Aggregation of symptoms of abdominal pain or bowel disturbance has been described in the families of patients with irritable bowel syndrome (IBS). This may be due to environmental factors, including learned responses to abdominal symptoms or a genetic contribution to the etiology of IBS. To determine the relative contribution of genetic factors to IBS by evaluating IBS symptoms in monozygotic (MZ) and dizygotic (DZ) twins. A total of 4,480 unselected twin pairs identified from a national volunteer twin register were asked to complete a validated questionnaire. IBS was defined by the Rome II criteria. A total of 5,032 subjects replied (56% response rate). One thousand eight hundred seventy complete twin pairs were evaluable; 888 MZ pairs (82 male pairs, mean age 51, SD 13 (range 19-81) yr) and 982 DZ pairs (69 male pairs, age 52, SD 13 (20-82) yr). The prevalence of IBS was 17% in MZ and 16% in DZ twins. There was no significant difference in casewise concordance rates between the MZ and DZ twins (28%vs 27%, p=NS). Logistic regression analysis revealed that decreasing age and increasing psychosomatic score were independently associated with IBS. Multifactorial liability threshold modeling suggested that a combination of unique and shared environmental factors provided the best model for IBS. In contrast, somatization was shown to be moderately heritable. Genetic factors are of little or no influence on IBS where the predominant influences appear to be environmental.

Simultaneous onset of mitral regurgitation requiring surgery due to primary chordal rupture in middle-aged identical twins

Primary chordal rupture is a leading cause of severe mitral regurgitation requiring surgery. It has previously been documented that there is a high probability of the occurrence of primary chordal rupture in patients with histological evidence of myxysomatous changes in the mitral valve. The precise etiology of primary chordal rupture and/or myxysomatous changes remains obscure and the relative contribution of genetic factors is debated. We report a pair of middle-aged identical twins requiring surgery for mitral regurgitation due to primary chordal rupture, and discuss the etiology of primary chordal rupture and/or myxysomatous changes.

Genetic Analysis of Candidate Modifier Polymorphisms in β-Thalassemia/Hb E Patients.

β-Thalassemia/Hb E patients encompass a number of clinical severities, ranging from nearly asymptomatic to transfusion-dependent thalassemia major. This has been well documented, but the causes of the variability and the molecular basis of the interaction remain unexplained. In general any factor capable of reducing the degree of alpha-globin-beta-globin chain imbalance will result in a milder form of thalassemia. The major modifying factors demonstrated in the mild cases are coinheritance of mild β+-thalassemia and Hb E genes, coinheritance of α-thalassemia and increased production of Hb F. However, the fact that many patients who have seemingly identical genotypes, β0-thalassemia/Hb E, and do not have a detectable α-thalassemia or increased Hb F production still have mild clinical symptoms, while other patients have a very severe clinical condition similar to homozygous β0-thalassemia. This variation suggests that other unknown modifying genetic factors may contribute to severity of the disease.To assess the relative contribution of genetic factors in the variation of severity among β-thalassemia/Hb E patients, we conducted a prospective study searching for modifying factors in almost 1100 Thai/Chinese β0-thalassemia/Hb E patients from Thailand using an automated, chip-based platform based on mass spectrometry (Sequenom's MassARRAYTM system). A map of ~80 single nucleotide polymorphisms (SNPs) has been constructed spanning more than 80 kb, including the locus control region (LCR) and all beta-like globin genes. These SNPs were identified through resequencing and from the public domain, including well-characterized restriction fragment length polymorphisms (RFLPs) used in prior haplotype studies. Included in this panel are assays for polymorphic sites reported to influence globin gene expression, specifically Gγ-Xmn I polymorphism and BP-1 binding site upstream of β-globin gene. Genotyping of other candidate modifier loci, including SNPs in genes encoding alpha hemoglobin stabilizing protein (AHSP), β-globin gene repressor BP-1 protein, erythropoietin (Epo), and transcription factors; GATA-1, EKLF, NF-E2, has been studied. To identify additional modifier loci, carefully selected patient sub-groups representing the extremes in disease severity either mild or severe have been selected for DNA pool construction to be used in a genomewide screen involving up to 100,000 validated gene-based SNPs. It is expected that this genomewide screen will yield important information on the role of candidate genes and may uncover the association of novel polymorphisms with severity heterogeneity in β-thalassemia/Hb E disease.

Electrocardiographic measures of left ventricular hypertrophy show greater heritability than echocardiographic left ventricular mass.

To assess the heritability (i.e. relative contribution of genetic factors to the variability) of continuous measures of left ventricular hypertrophy determined by electrocardiography and echocardiography. We studied 955 members of 229 Caucasian families, ascertained through a hypertensive proband. Electrocardiographic measurements were performed manually on resting 12-lead electrocardiograms, and echocardiographic measurements were made on M-mode images. Sex-specific residuals for the left ventricular phenotypes were calculated, adjusted for age, systolic blood pressure, weight, height, waist-hip ratio, and presence of diabetes. Heritability was estimated in two ways: firstly, from familial correlations with adjustment for spouse resemblance; and secondly by using variance components methods with ascertainment correction for proband status. The heritability estimates (given as a range derived from the two methods) were higher for Sokolow-Lyon voltage (39-41%) than for echocardiographic left ventricular mass (23-29%). Electrocardiographic left ventricular mass, Cornell voltage, and Cornell product had heritability estimates of 12-18%, 19-25%, and 28-32%, respectively. Genetic factors may explain a substantial proportion of variability in quantitative electrocardiographic and echocardiographic measures of left ventricular hypertrophy. The greater heritability of Sokolow-Lyon voltage suggests that electrocardiographic phenotypes may be particularly important for the molecular investigation of the genetic susceptibility to cardiac hypertrophy.

Genetics of peanut allergy: A twin study

Background: The role of genetics in the etiology of peanut allergy is unknown. For complex genetic traits, twin studies can provide information on the relative contribution of genetic factors to a disease, as the relative confounding effects of environmental factors are markedly decreased. Objective: This study was performed to search for evidence that genetic factors influence peanut allergy by comparing the concordance rate for this allergy among monozygotic and dizygotic twins. Methods: Twin pairs with at least one member with peanut allergy were ascertained through the Food Allergy Network by advertisements in the organization’s newsletters and Web site. Individuals with peanut allergy or parental surrogates were interviewed by telephone. A full atopic history was obtained, and peanut allergy and zygosity were determined using previously validated questionnaires. Heritability of peanut allergy was determined using univariate genetic model fitting by maximum likelihood with the Mx statistical modeling software package. Results: Seventy-five twin pairs were recruited. Seventeen pairs were excluded because of unconvincing peanut allergy histories (9 pairs, including 4 of uncertain zygosity) or because one twin had reportedly never ingested peanut (8 pairs). The median age of the 58 remaining twin pairs was 5 years (range 1 to 58 years). Seventy individuals had peanut allergy. In addition to convincing histories of peanut allergy, 52 (74%) had been tested (skin prick testing with or without radioallergosorbent assay) and all had positive reactions to peanut. Twenty-nine of the 70 had experienced >1 reaction to peanut; 29 of 70 had multisystem reactions. Among the monozygotic pairs (n = 14), 9 were concordant for peanut allergy (pairwise concordance, 64.3%) and among dizygotic pairs (n = 44), 3 were concordant for peanut allergy (pairwise concordance, 6.8%; χ2 = 21.38, P < .0001). Heritability of peanut allergy was estimated at 81.6% (95% confidence interval 41.6% to 99.7%) with model fitting using a population prevalence of peanut allergy of 0.4%. Conclusions: The significantly higher concordance rate of peanut allergy among monozygotic twins suggests strongly that there is a significant genetic influence on peanut allergy. (J Allergy Clin Immunol 2000;106:53-6.)

Genetic influences on F cells and other hematologic variables: a twin heritability study

To assess the relative contribution of genetic factors in the variation of F cells (FC) and other hematologic variables, we conducted a classical twin study in unselected twins. The sample included 264 identical (monozygotic [MZ]) twin pairs and 511 nonidentical (dizygotic [DZ]) same-sex twin pairs (aged 20 to 80 years) from the St. Thomas' UK Adult Twin Register. The FC values were distributed continuously and positively skewed, with values ranging from 0.6% to 22%. FC values were higher in women than in men and decreased with age, with the variables accounting for 2% of the total FC variance. The intraclass correlations of FC values were higher in MZ (rMZ = 0.89) than in DZ (rDZ = 0.49) twins. The XmnI-(G)gamma polymorphism in the beta-globin gene cluster had a significant effect on FC levels, accounting for approximately 13% of the total FC variance. Variance components analysis showed that the FC values were accounted for predominantly by additive genetic and nonshared environmental influences, with an estimate of heritability of 0.89. Hemoglobin levels and red blood cell, white blood cell, and platelet numbers were also substantially heritable, with heritability estimates of 0.37, 0.42, 0.62, and 0.57, respectively. Previously, studies of sib pairs with sickle cell disease and isolated family studies showed that high levels of Hb F and FC tend to be inherited. Here, our classical twin study demonstrated that the variance of FC levels in healthy adults is largely genetically determined. (Blood. 2000;95:342-346)

Genetic influences on F cells and other hematologic variables: a twin heritability study

AbstractTo assess the relative contribution of genetic factors in the variation of F cells (FC) and other hematologic variables, we conducted a classical twin study in unselected twins. The sample included 264 identical (monozygotic [MZ]) twin pairs and 511 nonidentical (dizygotic [DZ]) same-sex twin pairs (aged 20 to 80 years) from the St. Thomas' UK Adult Twin Register. The FC values were distributed continuously and positively skewed, with values ranging from 0.6% to 22%. FC values were higher in women than in men and decreased with age, with the variables accounting for 2% of the total FC variance. The intraclass correlations of FC values were higher in MZ (rMZ = 0.89) than in DZ (rDZ = 0.49) twins. The XmnI-Gγ polymorphism in the β-globin gene cluster had a significant effect on FC levels, accounting for approximately 13% of the total FC variance. Variance components analysis showed that the FC values were accounted for predominantly by additive genetic and nonshared environmental influences, with an estimate of heritability of 0.89. Hemoglobin levels and red blood cell, white blood cell, and platelet numbers were also substantially heritable, with heritability estimates of 0.37, 0.42, 0.62, and 0.57, respectively.Previously, studies of sib pairs with sickle cell disease and isolated family studies showed that high levels of Hb F and FC tend to be inherited. Here, our classical twin study demonstrated that the variance of FC levels in healthy adults is largely genetically determined. (Blood. 2000;95:342-346)

Ocular Dominance: Some Family Data

The most popular aspect of ocular dominance is sighting dominance or eye preference (eyedness). It refers to the preferential tendency of individuals looking through a telescope, microscope, or keyhole, or sighting along a gun. There is little work on the relative contribution of genetic factors to ocular dominance, so it is useful to review the available data from the literature and to present some new data. Eyedness was examined in a sample of 292 biologically related parent-offspring triads and 36 sibling pairs. The incidence of right eyedness amounted to 66.1%. There was a predominance of right-eyed male subjects over right-eyed female subjects. Analysis of the family study showed a significant correlation between parents and children. The frequency of left eyedness increased continuously with the number of left-eyed parents. These results imply that a genetic influence may operate to affect the direction of eye preference, although the data do not fit any straightforward recessive or dominant Mendelian model. It is possible that they are compatible with the type of model invoking fluctuating asymmetry which has been used to explain the inheritance of other aspects of laterality.

Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12.

Crohn's disease (CD) and ulcerative colitis (UC), the chronic inflammatory bowel diseases (CIBD), are common causes of gastro-intestinal disease in the Western world, with a combined prevalence of 100-200/100,000 (ref. 1). Epidemiological studies, particularly concordance rates in twin pairs and siblings, strongly implicate genetic susceptibility in the pathogenesis of CIBD. In fact, the relative contribution of genetic factors to the pathogenesis of CD may be greater than in schizophrenia, asthma or hypertension, and at least equivalent to that in insulin-dependent diabetes. Systematic screening of the entire human genome now provides a strategy for the identification of susceptibility genes in complex polygenic disorders. We undertook a two-stage genome search for susceptibility genes in inflammatory bowel disease involving 186 affected sibling pairs from 160 nuclear families. We provide strong evidence for the presence of susceptibility loci for both CD and UC on chromosome 3, 7 and 12. We obtained the highest lod score (5.47; P = 2.66 x 10(-7) with the marker D12S83 and lod scores of 3.08 and 2.69 for D7S669 and D3S1573, respectively. Our data suggest that CD and UC are closely related, but distinct, polygenic disorders that share some, but not all, susceptibility genes.

Biliary lipid composition in monozygotic and dizygotic pairs of twins.

The relative contribution of genetic factors to biliary and serum lipid composition was studied in 17 monozygotic and 18 dizygotic middle aged male pairs of twins. Cholesterol precursors, squalene and Methylated sterols which reflect the activity of cholesterol synthesis were also measured. Pairwise intraclass correlations were determined for monozygotic and dizygotic twin pairs and heritability estimates were calculated. Molar % of biliary cholesterol and percentage distribution of biliary cholic acid and particularly deoxycholic acid showed significant pairwise correlations within the monozygotic but not the dizygotic pairs. Similar correlations were found for total biliary methylsterols and of the methylsterol subfractions for the two methostenols but not for squalene, lanosterol and dimethylsterols. In serum, the precursor sterols, but not squalene, showed even higher pairwise correlations in the monozygotic twins than the corresponding precursors in bile. Molar per cent of bile acids and phospholipids and cholesterol saturation index were not correlated significantly in either twin pairs, but the pairwise correlations tended to be higher in the monozygotic than in the dizygotic pairs. Gall stones were found in seven monozygotic and three dizygotic subjects. Two monozygotic twin pairs were concordant for gall stones; all the dizygotic pairs were discordant. Overall, these data suggest that molar percentage of biliary cholesterol, bile acid composition, cholesterol synthesis, bile cholesterol saturation, and gall stone formation may be under a significant genetic control.