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PubMed1976

Parent-offspring resemblances in intelligence: theories and evidence.

A review of data on parent-offspring resemblances in intelligence is presented in the context of correlation, regression and variance predictions from the polygenic model and an environmental model. Consideration was given to reliability, test equivalence and long-term stability of IQ scores. Results indicate that much of the difference among offspring IQ scores is not directly attributable to parental IQ, and that some is due to other between-family variables. The magnitude of single-parent-offspring correlations was related to the degree of assortative mating present in samples. Evidence on whether parent-offspring resemblances in IQ are transmitted genetically or environmentally is on the whole lacking. A single study provides evidence for some degree of genetic transmission, but it is argued that the present polygenic model is inadequate.

Age Factors↗

PubMed1972

Genetic control of host responses to endotoxin.

Two pathophysiological effects of endotoxin in mice have been shown to be under the major influence of polygenic inheritance. The first, endotoxemia, was measured by LD(50) assays on hybrids and backcross hybrids of the resistant C(3)H/HeJ and the susceptible A/HJe strains. The LD(50) values of the F1 hybrids and the backcross hybrids were intermediate between the respective parental types. The second effect, the intraperitoneal extravascular leukocyte response to small doses of endotoxin, also was found to follow characteristic patterns of polygenic inheritance. As estimated from an analysis of the variance of mice of the F1 and F2 generations, the degree of genetic determination is approximately 54% for the neutrophil response and 82% for the monuclear response.

Animals↗

PubMed1970

Genetic control of phenylbutazone metabolism in man.

The purposes of the present investigation were to assess the genetic contribution to thevariability between individuals in the rate at which they metabolize phenylbutazone and to characterize the type of inheritance that controls the metabolism of the drug. The 155 persons investigated included 43 unrelated random individual subjects and the members of 28 two-generation family units. None of these subjects had taken drugs in the six months preceding the experiments. Each subject ingested an oral dose of phenylbutazone and the plasma half-life of the drug was determined. These non-pretreated plasma phenylbutazone half-lives suggest the existence of polygenic control, but the value of the data is marred by the frequency distribution being very skewed.The 142 persons given a second test, included 41 unrelated random subjects and 24 two-generation family units. A three-day course of oral phenobarbitone was followed by an oral dose of phenylbutazone and the plasma half-life of the latter determined. The phenobarbitone was given with the aim of "inducing" drugmetabolizing enzymes in the liver, thus rendering the environment more uniform. When the post-phenobarbitone half-lives were adjusted to a standard height they were approximately normally distributed. There was a significant regression of mean offspring value on mid-parent value, indicating that about 65% of the observed phenotypic variance of post-phenobarbitone plasma phenylbutazone half-lives is due to the additive effects of genes.Phenylbutazone metabolism in man is thus shown to be under polygenic control, and genetically controlled in a similar manner and to a similar degree to body height.Improved understanding of phenylbutazone metabolism may lead to improved therapeutic efficacy and a lower incidence of adverse reactions.

Body Height↗

PubMed2026

Metabolomic ageing across mental and behavioural disorders.

BACKGROUND: Individuals with mental disorders face excess morbidity and premature mortality. Accelerated ageing has been proposed as a contributing mechanism but population-scale evidence across diverse diagnoses is limited. OBJECTIVE: To examine whether metabolomic ageing differs across mental disorders and whether associations vary by sex, age group and genetic liability. METHODS: Using plasma metabolomic profiles from UK Biobank participants, we applied a metabolomic ageing clock (MileAge) to estimate disorder-specific differences between metabolite-predicted and chronological age. Mental disorders were ascertained from health records and self-reported physician diagnoses. We analysed nine diagnostic groups and 45 individual disorders and assessed sex and age group differences and associations with polygenic scores. FINDINGS: Among 225 212 participants (54% female; mean age 56.97), 38 524 had a diagnosis preceding baseline. Substance use, psychotic, affective and neurotic disorders were associated with a metabolite-predicted age older than chronological age, largest for psychosis (β=0.556, 95% CI 0.250 to 0.861, p<0.001). Obsessive-compulsive and eating disorders were associated with a metabolite-predicted age younger than chronological age. Several associations were stronger in males and in individuals aged <65 years. Higher genetic liability to depression, autism and attention-deficit/hyperactivity disorder predicted an older metabolomic age (β range=0.020 to 0.047), whereas polygenic scores for psychosis and tobacco use disorder predicted a younger metabolomic age (β range=-0.023 to -0.040). For obsessive-compulsive disorder and anorexia nervosa, clinical and genetic associations indicated younger metabolomic ageing. CONCLUSIONS: Metabolomic ageing in mental disorders is heterogeneous. While many disorders are associated with an older biological age, some are linked to a younger biological age. Divergence between genetic liability and clinical phenotypes suggests that non-genetic factors shape biological ageing differences. CLINICAL IMPLICATIONS: Biological age should not be assumed to uniformly exceed chronological age across mental disorders. Sex and age-specific approaches could improve understanding of biological ageing processes in psychiatry.

Humans↗

PubMed1993

Familial aggregation of idiopathic dilated cardiomyopathy: clinical features and pedigree analysis in 14 families.

OBJECTIVE: A recent prospective study in patients with dilated cardiomyopathy has reported that the disease is familial in at least 20% of cases, but the pattern of inheritance could not be ascertained. The presence of an autosomal dominant pattern, such as seen in hypertrophic cardiomyopathy, could make it possible to search for single gene defects with linkage analysis, whereas polygenic inheritance would be consistent with the autoimmune hypothesis. To assess the pattern of inheritance, we retrospectively identified patients with familial disease and assessed their first degree relatives (parents, siblings and children) for dilated cardiomyopathy. DESIGN AND PATIENTS: The family history of 105 consecutive patients with dilated cardiomyopathy was reviewed and 14 who had at least one first degree relative with documented disease were identified as probands. Their healthy relatives (109) were studied by physical examination, electrocardiography, M mode and cross sectional echocardiography, and were classified as unequivocally normal or as potential carriers. The potential carriers had abnormal electrocardiography with either at least one echocardiographic measurement of left ventricular cavity dimension or percentage fractional shortening outside 2 SDs of normal values (based on age and body surface area). The potential carriers underwent 24 hour Holter monitoring and maximal treadmill exercise. RESULTS AND CONCLUSION: Twenty three relatives (21%) were classified as potential carriers: 12 had an increased left ventricular end diastolic dimension, with reduced percentage fractional shortening in three; 11 had an abnormal electrocardiogram and increased end diastolic dimension, with reduced percentage fractional shortening in five. Such abnormalities were very mild and follow up is necessary to find whether such changes represent early disease. Pedigree analysis was most consistent with polygenic inheritance.

Adolescent↗

PubMed1987

Molecular pathology of single gene disorders.

Recent studies using recombinant DNA technology have led to an understanding of the basic molecular pathology of single gene disorders. Furthermore, methods are being developed for finding genes for conditions, whose underlying biochemistry is still not understood, or which may contribute to polygenic systems that underlie common diseases. As well as providing new approaches to carrier detection, prenatal diagnosis, and treatment of single gene disorders, these advances promise to provide important information about the pathophysiology of many common polygenic diseases.

Chromosome Aberrations↗

PubMed1988

Clinical and laboratory responses to niceritrol in the treatment of hypercholesterolaemia.

Twenty-five hypercholesterolaemic patients from three centres in the UK were investigated in an open study of the efficacy and side effects of niceritrol. Five patients dropped out of the study at an early stage and had insufficient data for analysis. There were 13 males and 7 females (mean age 49.2 years, range 18-69). Fourteen patients had heterozygous familial hypercholesterolaemia, and six polygenic hypercholesterolaemia. Niceritrol was started at a dose of 750 mg/day and this was increased at weekly intervals over 4 weeks to the maximum tolerated dosage up to 3 g/day. This was then maintained for a further 8 weeks. There were statistically significant decreases in total plasma cholesterol, total triglyceride, LDL cholesterol and VLDL triglyceride; HDL cholesterol remained unchanged after 12 weeks of treatment (Wilcoxon matched pairs, signed ranks test). The 14 patients with familial hypercholesterolaemia showed a 13.9% fall in total cholesterol and a 19.8% fall in LDL cholesterol. All patients reported flushing and some had gastrointestinal symptoms but 19 would have been prepared to continue with the therapy at doses up to 3 g/day. Thus niceritrol has been found to be beneficial in the treatment of both familial and polygenic hypercholesterolaemia.

Adolescent↗

PubMed2003

Identification of ISSR markers associated with productivity traits in silkworm, Bombyx moni L.

Bombyx mori L., commonly recognised around the world as the mulberry silkworm, is characterized by a wide variability in yield and developmental traits, which have been proven through conventional genetic analysis to be of polygenic nature. A large number of morpho-biochemical traits and RFLP and RAPD markers are mapped on different linkage groups, but to this point very little attention has been given to unravelling the genetics of yield traits. To address this issue, polymorphic profiles of 147 markers generated with 12 ISSR primers on the genomic DNA of 20 silkworm stocks of diverse yield status were subjected to multiple regression and discriminant function analyses (DFA). This led to the identification of eight markers generated by six primers, which demonstrated high beta-coefficient indices of -0.451 to -0.940. Furthermore, a significant difference between the yield traits for stocks with and without the specific marker could also be established. The inheritance pattern of one marker, L13800bp, identified at the first step of selection of markers through stepwise regression analyses for five yield parameters is discussed in the context of applying multiple regression analysis for establishing association, if not linkage, between a group of DNA markers and a particular yield trait of polygenic nature and using such markers in molecular marker-assisted breeding programs.

Analysis of Variance↗

PubMed2003

A new obesity-prone, glucose-intolerant rat strain (F.DIO).

Previous breeding for the diet-induced obese (DIO) trait from outbred Sprague-Dawley rats produced a substrain with selection characteristics suggesting a polygenic mode of inheritance. To assess this issue further, selectively bred DIO male rats were crossed with obesity-resistant inbred Fischer F344 dams. Male offspring were crossed twice more against female F344 dams. The resultant N3 (F.DIO) rats were then inbred three more times. On low-fat chow, 10-wk-old male and female DIO rats weighed 86 and 59% more than respective F344 rats. By the N3 (F.DIO) generation, they were only 12 and 10% heavier, respectively. After three additional inbreeding cycles, chow-fed F.DIO males had an exaggerated insulin response to oral glucose compared with F344 rats. After 3 wk on a 31% fat (high-energy) diet, male N3 F.DIO rats gained 16-20% more carcass and adipose weight with 98% higher plasma leptin levels, whereas F.DIO females gained 36-54% more carcass and adipose weight with 130% higher leptin levels than comparable F344 rats. After three inbreeding cycles, F.DIO males still gained more weight on high-energy diet and developed a threefold greater insulin response to oral glucose than F344 males. Preservation of the DIO and glucose intolerance traits through successive backcrosses and inbreeding cycles to produce the F.DIO strain lends further support to the idea that they inherited in a polygenic fashion.

Animals↗

PubMed2005

Genetic determinants of weight of fast- and slow-twitch skeletal muscle in 500-day-old mice of the C57BL/6J and DBA/2J lineage.

C57BL/6J (B6) and DBA/2J (D2) strains and two derivative populations, BXD recombinant inbred strains (BXD RIs) and B6D2F2, were used to explore genetic basis for variation in muscle weight at 500 days of age. In parallel with findings in 200-day-old mice (Lionikas A, Blizard DA, Vandenbergh DJ, Glover MG, Stout JT, Vogler GP, McClearn GE, and Larsson L. Physiol Genomics 16: 141-152, 2003), weight of slow-twitch soleus, mixed gastrocnemius, and fast-twitch tibialis anterior (TA) and extensor digitorum longus (EDL) muscles was 13-22% greater (P < 0.001) in B6 than in D2. Distribution of BXD RI strain means indicated that genetic influence on muscle weight (strain effect P < 0.001, all muscles) was of polygenic origin, and effect of genetic factors differed between males and females (strain-by-sex interaction: P < 0.01 for soleus, EDL; P < 0.05 for TA, gastrocnemius). Linkage analyses in B6D2F2 population identified QTL affecting muscle weight on Chr 1, 2, 6, and 9. Pleiotropic influences were observed for QTL on Chr 1 (soleus, TA), 2 (TA, EDL, gastrocnemius), and 9 (soleus, TA, EDL) and were not related to muscle type (fast/slow-twitch) or function (flexor/extensor). Effect of QTL on Chr 9 on soleus muscle was male specific. QTL on Chr 2 and 6 were previously observed at 200 days of age, whereas QTL on Chr 1 and 9 are novel muscle weight QTL. In summary, muscle weight in B6/D2 lineage is affected by a polygenic system that has variable influences at different ages, between males and females, and across muscles in a manner independent of muscle type.

Aging↗

PubMed2006

Sex-specific QTLs and interacting loci underlie salt-sensitive hypertension and target organ complications in Dahl S/jrHS hypertensive rats.

Sex-specific differences in polygenic (essential) hypertension are commonly attributed to the role of sex steroid hormone-receptor systems attenuating sex-common disease mechanisms in premenopausal women. However, emerging observations indicate sex-specific genetic susceptibility in various traits, thus requiring systematic study. Here we report a comparative analysis of independent total genome scans for salt-sensitive hypertension susceptibility quantitative trait loci (QTLs) in male and female F2 [Dahl R/jrHS x S/jrHS] intercross rats exposed to high-salt (8% NaCl) rat diets. Hypertension was phenotyped with three quantitative traits: blood pressure (BP) elevation associated with increased hypertensive renal disease [glomerular injury score (GIS)] and increased cardiac mass [relative heart weight (RHW)] obtained 8-12 wk after high-salt challenge; 24-h nonstress, telemetric BP measurements were used. Although sex-common QTLs were detected for BP [chromosome (chr) 1-144.3 Mbp; chr 1-208.8 Mbp], GIS (chr 1-208.8 Mbp), and cardiac mass (chr 5-150.3 Mbp), most QTLs across the three phenotypes studied are gender specific as follows: female QTLs for BP (chr 2-106.7 Mbp, chr 2-181.7 Mbp, chr 5-113.9 Mbp, chr 5-146.7 Mbp, chr 12-12.8 Mbp), GIS (chr 15-59.6 Mbp), and RHW (chr 2-31.5 Mbp, chr 5-154.7 Mbp, chr 5-110.9 Mbp); male QTLs for BP (chr 2-196.7 Mbp, chr 11-48.0 Mbp, chr 20-35.7 Mbp), GIS (chr 6-3.3 Mbp, chr 20-40.7 Mbp), and RHW (chr 6-3.3 Mbp, chr 20-40.7 Mbp). Furthermore, interacting loci with significant linkage were detected only in female F2 intercross rats for BP and hypertensive renal disease. Comparative analyses revealed concordance of BP QTL peaks with previously reported rat model and human hypertension susceptibility genes and with BP QTLs in previous Dahl S-derived F2 intercross studies and also suggest strain-specific genetic modifiers of sex-specific determinants. Altogether, the data provide key experimental bases for sex-specific investigation of mechanisms and intervention and prevention strategies for polygenic hypertension in humans.

Animals↗

PubMed2002

Two new recursive likelihood calculation methods for genetic analysis.

Recursive likelihood calculations for genetic analysis with ungenotyped pedigree data employ variations of the Elston-Stewart (ES) or the Lander-Green (LG) algorithms. With the ES algorithm, the number of loci may be limited but not the pedigree size. With the LG algorithm, the reverse is the case. We introduce two new algorithms for the computation of regressive likelihoods for pedigrees with multivariate traits. The first is an alternative formulation of our existing model, which leads to a simpler form in the binary trait, polygenic and mixed model cases. The second is an approximation model, which is computationally efficient. These methods apply to both continuous and binary traits, in the oligogenic and polygenic cases. Both methods coincide in the binary case. We considered these methods for cases in which all the traits are controlled by a single locus, with each trait controlled by one locus independent to the others. Simulation studies and analysis of a real data are presented for segregation analysis as illustrations. These methods can also be used in other model-based analyses. These methods are implemented in G.E.M.S., the genetic epidemiology models software.

Animals↗

PubMed1990

Variability of pulmonary function in alpha-1-antitrypsin deficiency: residual family resemblance beyond the effect of the Pi locus.

To gain insight into the variable expression of lung disease in alpha 1-antitrypsin deficiency, two pulmonary function tests, FEV1 and FEF25-75, were examined in alpha 1-antitrypsin-deficient individuals and their families. The mean and variance effects of Pi type, age, and sex on the pulmonary function variables were removed by stepwise multiple regression, and the residual phenotypes were analyzed. Path analysis of the residual phenotypes with environmental indices in 46 nuclear families demonstrated highly significant cultural inheritance. Significant polygenic inheritance was not demonstrated for FEV1 but was shown for FEF25-75. For FEV1, adjustment for the significant interaction between Pi type and pack-years of smoking tended to increase the estimated contribution of polygenic inheritance and to decrease the estimated contribution of cultural inheritance. Segregation analysis of the residual phenotypes in 44 nuclear families was carried out to determine whether another major gene, other than the Pi locus, may be influencing pulmonary function in this population. Statistical evidence was found for an additional major gene influencing FEV1; however, the evidence diminished after adjusting for the effects of pack-years and the interaction between Pi type and pack-years. This apparent drop in the importance of genetic factors would not be surprising if the effect of the putative major gene is to enhance susceptibility to effects of cigarette smoking. Finally, our investigation demonstrates the feasibility of dissecting residual familial effects on complex multifactorial traits.

Factor Analysis, Statistical↗

PubMed1992

The Elston-Stewart algorithm for continuous genotypes and environmental factors.

The Elston-Stewart algorithm for a normally distributed trait under a polygenic model is explained in detail and extended to allow for other continuous environmental variables. This formulation is especially useful for large pedigrees, as it avoids the need to invert matrices. Whereas it may not be feasible by this method to estimate all the various components of previously suggested models for polygenic inheritance, it can allow for a reasonably flexible pedigree correlational structure under which valid tests can be performed for fixed effects that may affect the phenotype.

Algorithms↗

PubMed1991

Dissecting the primary causes of genetic hypertension in rats.

Blood pressure has a genetic component influenced by several to many genetic loci in both humans and animals; that is, blood pressure is a polygenic trait. Ultimately, the primary causes of genetic hypertension can only be established with genetic techniques. The primary tools for this analysis in animals are inbred strains of rodents selectively bred for differences in blood pressure and the genetic analysis of these strains by cosegregation techniques. This analysis determines whether it is possible to separate specific alleles at a candidate genetic locus from a component of blood pressure in genetically segregating populations. If the candidate alleles cosegregate with a component of blood pressure, these alleles must be the cause of the blood pressure differences or be linked on the same chromosome to alleles at other loci that cause blood pressure differences. If, on the other hand, the candidate alleles do not cosegregate with blood pressure, they cannot be the cause of the blood pressure differences. This analysis is straightforward in the case of a single-locus Mendelian candidate trait but is less informative if a candidate trait is itself polygenic. In this case, genetic analysis yields either 1) results that are compatible with, but not definitive proof for, a genetic role of the trait in causing blood pressure differences or 2) results that eliminate the trait as a cause of genetic differences in blood pressure. A complete listing of all the traits that have undergone genetic cosegregation analysis in rodents is given.

Animals↗

PubMed2000

Genes and hypertension: from gene mapping in experimental models to vascular gene transfer strategies.

Human essential hypertension is a complex, multifactorial, quantitative trait under a polygenic control. Several strategies have been developed over the last decade to dissect genetic determinants of hypertension. Of these, the most successful have been studies that identified rare mendelian syndromes in which a single gene mutation causes high blood pressure. The attempts to identify multiple genes, each with a small contribution to the common polygenic form of hypertension, have been less successful. Several laboratories focused their attention on rat models of genetic hypertension, which can be considered as a reductionist paradigm for human disease. Using numerous crosses between hypertensive and normotensive strains, investigators identified several quantitative trait loci (QTL) for blood pressure subphenotypes and for cardiovascular complications such as left ventricular hypertrophy, kidney failure, stroke, and insulin resistance. Furthermore, congenic strains have been produced to confirm the existence of some of these QTL and to narrow down the chromosomal regions of interest. A number of interesting strategies have been developed, including a "speed" congenic strategy perfected by our group in Glasgow. However, the limit of congenic strategy is estimated at 1 cM, which corresponds to 2x10(6) base pairs of DNA and approximately 50 candidate genes. It is envisaged that gene expression profiling with cDNA microarrays might allow a quick progression toward the gene identification within cardiovascular QTL. In parallel experimental effort, several laboratories have been developing gene transfer/therapy strategies with adenoviral or adeno-associated viral vectors used, for example, to overexpress protective vascular genes such as vascular endothelial growth factor or endothelial nitric oxide synthase. It is anticipated that further developments in positional cloning of susceptibility and severity genes in hypertension and its complications will lead to a direct transfer of these discoveries to essential hypertension in humans and will ultimately produce novel targets for local and systemic gene therapy in cardiovascular disease.

Animals↗

PubMed2000

Renin-angiotensin system polymorphisms and coronary events in familial hypercholesterolemia.

The role of renin-angiotensin system polymorphisms as risk factors for coronary heart disease (CHD) is controversial. This study investigated their role in patients with heterozygous familial hypercholesterolemia (FH). Polymorphism frequencies for angiotensin-I-converting enzyme insertion/deletion (ACE I/D), angiotensinogen M235T, and angiotensin-II type I receptor (AG2R) A1166C were determined in 112 patients with FH and 72 patients with polygenic hypercholesterolemia, of whom 26.7% and 41.6%, respectively, had established CHD. None of the polymorphisms were associated with risk of CHD in patients with polygenic hypercholesterolemia in this study. Logistic regression analysis of risk factors for CHD in patients with FH identified male sex (odds ratio [OR]=3.03; 95% CI, 3.07 to 3.72; P=0.05), smoking (OR=2.91; 95% CI, 2.16 to 4.24; P=0.05), diastolic blood pressure (OR=3.70; 95% CI, 3.43 to 3.97; P=0.02), plasma glucose (OR=3.31; 95% CI, 3. 10 to 3.52; P=0.04), and the AG2R A1166C polymorphism as risk factors. The OR for the AG2R A1166C polymorphism was 2.26 (95% CI, 1.26 to 3.72; P=0.06) and increased to 3.10 (95% CI, 1.20 to 7.52; P=0.04) after adjustment for other risk factors. The AG2R A1166C polymorphism may interact with severe hypercholesterolemia and other risk factors to increase risk of CHD in FH patients.

Adult↗

PubMed2001

Genome-wide linkage analysis of pulse pressure in Mexican Americans.

Pulse pressure, a measure of aortic stiffness, is a strong predictor of cardiovascular mortality. To locate genes that affect pulse pressure, we performed genetic analysis on randomly ascertained families in the San Antonio Family Heart Study. Pulse pressure was defined as the difference between systolic and diastolic blood pressures. Likelihood methods were used to construct a model that had both single-locus and polygenic components for 46 families (1308 individuals). The single-locus component included sex-specific and genotype-specific effects of both age and body mass index. Using this model, we then performed 2-point linkage analysis in 10 families (440 individuals) that were among the largest of the 46 families and that had been genotyped for 399 polymorphic markers. The model that contained only the polygenic component and simple effects of the covariates showed pulse pressure heritability of 0.21. When the single-locus component was added, the sex-specific and genotype-specific effects of age and body mass index were highly significant (P<0.002). The full model accounted for 73% of the total variation of pulse pressure. Linkage analysis using this model with each marker revealed 4 markers with lod scores >1.9, which is the Lander-Kruglyak suggestive linkage standard. D21S1440 had a lod score of 2.78 with a recombination fraction (theta) of 0.02. D7S1799 had a lod score of 2.04 (theta=0.01), D8S1100 had a lod score of 1.98 (theta=0.08), and D18S844 had a lod score of 1.95 (theta=0.11). These results are highly correlated with results involving systolic blood pressure, indicating that pulse pressure may not be genetically distinct from systolic blood pressure.

Adolescent↗