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PubMed1982

The assessment of Achilles tendon size in primary hypercholesterolaemia by computed tomography.

The Achilles tendons of 43 men and women were examined by conventional radiography and by computed tomography (CT). Eleven subjects were normolipidaemic and 32 had familial hypercholesterolaemia, of whom 19 were considered to have polygenic hypercholesterolaemia and 13 monogenic. Achilles tendon xanthomata were identifiable by both radiography and CT. In assessing the size of xanthomata, CT had advantages since the junction between muscle and tendon was easily identified and all the dimensions and the cross-sectional area of the tendon could be measured. The area of Achilles tendons was closely correlated with body height in normolipidaemic men and women and patients with polygenic hypercholesterolaemia. In monogenic hypercholesterolaemia this relationship was lost. The tendons of the normolipidaemic group and of patients with polygenic hypercholesterolaemia were indistinguishable, whereas those of patients with monogenic hypercholesterolaemia were significantly larger. Neither the maximum nor the average CT attenuation values of the tendons differed significantly between the 3 groups. Of the patients with monogenic hypercholesterolaemia, those whose Achilles tendons were less than 200 mm2 in area had received treatment longer than those with larger tendons. CT shows promise as a means of assessing the therapeutic response of patients with monogenic familial hypercholesterolaemia.

Achilles Tendon↗
PubMed1989

Segregation and linkage analyses of bipolar and major depressive illnesses in multigenerational pedigrees.

Data were collected on six large multigenerational pedigrees, four ascertained through a proband with major depression and two ascertained through a proband with a bipolar form of illness. Diagnoses were made using the SADS-L structured interview and Research Diagnostic Criteria (RDC). Complex segregation analyses were conducted on the bipolar and the major depression pedigree sets using a model allowing for both major locus and polygenic inheritance; in these analyses a variety of diagnostic schemes and assumptions concerning the lifetime population prevalence were examined. Linkage analyses on standard markers were conducted using parameters for transmission of susceptibility to illness derived from the segregation analyses. Results of the segregation analyses were quite sensitive to the diagnostic and prevalence assumptions. In the pedigrees ascertained through probands with a bipolar form of illness, we were unable to discriminate between major gene and polygenic inheritance. The data were compatible with Mendelian major gene transmission of susceptibility to illness when bipolar and schizoaffective manic diagnoses were considered as affected and the lifetime population prevalence was between 0.04 and 0.06. Outside this narrow prevalence range, or when additional diagnoses, such as major depression or hypomania, were included as expressions of liability to disease, major gene transmission of susceptibility to disease could be rejected. Similarly, in the pedigrees ascertained through probands with major depression, it was not generally possible to discriminate between major gene and polygenic transmission of susceptibility to illness. For a diagnostic scheme including only major depression as a manifestation of susceptibility to illness, there was a narrow range of lifetime population prevalence values (female prevalence ranging from 0.20 to 0.25, male prevalence set to 1/2 female prevalence) which yielded results compatible with major gene transmission. Linkage analyses for all markers yielded negative or inconclusive results. In one bipolar pedigree a lod score of 1.65 was found with a marker in chromosome 1 recommending further studies of this chromosome.

Adult↗
PubMed2005

Genetics of type 2 diabetes mellitus.

The clinical picture of type 2 diabetes mellitus (T2DM) is formed by impairment in insulin secretion and resistance to insulin action. As a result of intensive efforts of the scientists around the world mutations and polymorphisms in a number of genes were linked with monogenic and polygenic forms of T2DM. Two major strategies were used in this research: genome scanning and the candidate gene approach. Monogenic forms, despite their rarity, constitute a field where substantial progress has been made in the dissection of the molecular background of T2DM. Monogenic forms of T2DM with profound defect in insulin secretion include subtypes of maturity onset diabetes of the young (MODY), maternally inherited diabetes with deafness (MIDD) caused by mitochondrial mutations, and rare cases resulting from insulin gene mutations. The majority of proteins associated with MODY are transcription factors, such as hepatocyte nuclear factor 4alpha (HNF-4alpha), HNF-1alpha, insulin promoter factor-1 (IPF-1), HNF-1beta, and NEUROD1. They influence expression of the other genes through regulation of mRNA synthesis. Only MODY2 form is associated with glucokinase, a key regulatory enzyme of the beta cell. There are striking differences in the clinical picture of MODY associated with glucokinase and MODY associated with transcription factors. Three monogenic forms of T2DM characterized by severe insulin resistance are the consequence of mutations in the PPARgamma, ATK2, and insulin receptor genes. Patients with monogenic T2DM, particularly with MODY, sometimes, develop discrete extra-pancreatic phenotypes; for example, lipid abnormalities or a variety of cystic renal diseases. Efforts aiming to identify genes responsible for more common, polygenic forms of T2DM were less effective. These forms of T2DM have a middle/late age of onset and occur with both impaired insulin secretion and insulin resistance. Their clinical picture is created by the interaction of environmental and genetic factors, such as frequent polymorphisms of many genes, not just of one. These polymorphisms may be localized in the coding or regulatory parts of the genes and are present, although with different frequencies, in T2DM patients as well as in healthy populations. Sequence differences in a few genes have been associated, so far, with complex, polygenic forms of T2DM, for example, calpain 10, PPARgamma, KCJN11, and insulin. In addition, some evidence exists that genes, such as adiponectin, IRS-1, and some others may also influence the susceptibility to T2DM. It is expected that in the nearest future more T2DM susceptibility genes will be identified.

Diabetes Mellitus, Type 2↗
PubMed2026

Monogenic ALB Variants as Determinants of Severe Hypercholesterolemia: A Population-Based Cohort Study.

BACKGROUND: Hypoalbuminemia is associated with several risk factors for myocardial infarction, including hypercholesterolemia, liver disease, kidney disease, and diabetes. Homozygosity of loss-of-function (LoF) variants in the ALB gene, which encodes albumin, is a known cause of congenital hypoalbuminemia. Studies have also shown that heterozygous ALB LoF variants are associated with increases in low-density lipoprotein cholesterol (LDL-C), comparable to those seen in familial hypercholesterolemia. OBJECTIVES: This study examined the effect of ALB LoF variants and other causes of low albumin on LDL-C levels in 2 population biobanks. METHODS: This study used data from 2 large cohorts with linked electronic health record and genetic information: Geisinger's MyCode Community Health Initiative, a health care population based in Pennsylvania, USA; and the National Institutes of Health All of Us Research Program, a nationwide epidemiologic cohort. LDL-C values were adjusted for lipid-lowering medication use. Myocardial infarction diagnoses were extracted from electronic health records using International Classification of Diseases codes. A polygenic score for serum albumin was calculated for participants of European ancestry. Linear regression models were used to estimate associations, and results were meta-analyzed across cohorts using fixed-effects models. RESULTS: Among 155,530 MyCode and 405,701 All of Us adult participants, 77 individuals (1 of 7,289) carried an ALB LoF variant. Among noncarriers, a 1 g/dL decrease in serum albumin was associated with a 10.9 mg/dL (95% CI:, 10.4-11.4) decrease in LDL-C. In contrast, ALB LoF variants were associated with a 0.69 g/dL (95% CI: 0.60-0.78) reduction in serum albumin and a 38.3 mg/dL (95% CI: 28.2-48.5) increase in LDL-C. Paradoxically, whereas monogenic determinants of hypoalbuminemia were associated with increased LDL-C, polygenic determinants of lower albumin were associated with a 0.22 mg/dL (95% CI: 0.17-0.26) decrease in LDL-C per decile. CONCLUSIONS: ALB LoF variants represent a previously underrecognized monogenic cause of elevated LDL-C, with effect sizes slightly less than canonical familial hypercholesterolemia variants. The divergent effects of ALB-mediated vs polygenic or physiological reductions in albumin on LDL-C suggest distinct underlying mechanisms.

Humans↗
PubMed2001

Genetic epidemiology of multistage carcinogenesis.

It is commonly believed that cancer is a multistage, polygenic disease. Even though conceptually appealing, the evidence supporting the multistage theory remains limited. Most known tumor suppresser genes are associated with monogenic dominant cancers following a two-hit pathway. We review results from a recent twin study on 90000 individuals that give support to the multistage theory. Statistically significant heritability estimates were shown for cancers of the colorectum (35%), breast (27%), and prostate (42%). These estimates are much higher than those obtained from family studies in which parents and offspring, or sibs are compared. The difference can be accounted for by the involvement of many genes. A polygenic cancer would show small effects in family studies but large effects in twin studies. We present calculations on the decrease in familial risks when the number of genes involved increases or when the penetrance decreases. We test the apparent number of stages involved in the main cancers from the Swedish Family-Cancer Database. The logarithms of the slopes suggest large differences in the apparent numbers of mutations involved in different cancers. The number of mutations required appears to be less in familial breast cancer compared to sporadic breast cancer. Study designs for gene identification should be revised to accommodate polygenic cancers.

Databases, Factual↗
PubMed1997

The genetic analysis of multiple sclerosis.

Although monogenic diseases often show extreme clinical phenotypes, the major burden of genetic ill health lies in the more prevalent polygenic disorders, such as diabetes, hypertension and multiple sclerosis. These conditions affect many thousands of individuals and their management consumes vast amounts of health care resources: in the UK some 80,000 people have multiple sclerosis; the estimated financial cost to society of introducing treatments, such as beta interferon, could be as high as 250 million pounds per year. Knowledge on the genetics of these common diseases is poor, but has potentially received a considerable boost with the arrival of whole genome screening. The genome screen in insulin-dependent diabetes mellitus (IDDM) reported in 1994 was the first in a human polygenic disease. Since this publication, whole genome screening has been performed in a variety of human polygenic diseases, including schizophrenia, bipolar affective disorder, non-insulin-dependent diabetes mellitus (NIDDM), inflammatory bowel disease, asthma and multiple sclerosis.

Americas↗
PubMed2000

Genetic variability in milking speed of dairy goats.

The present investigation deals with the genetic variability of milking speed, measured as the volume of milk collected during the first minute of milking (MD1), and its association with dairy traits. Data originated from 2589 lactations of 1421 Alpine goats, sired by 93 bucks, measured between 1985 and 1997 at the Moissac Goat Experimental Station (Lozère, France). Two genetic analyses were carried out. Firstly, a polygenic model was used to estimate genetic and phenotypic parameters among milking speed and dairy traits using a multiple-trait animal model. Secondly, segregation analysis was used to test the hypothesis of mixed model inheritance (polygenes + major gene) for MF1. Heritability and repeatability of MF1 under the polygenic model were high (0.65 and 0.82, respectively). Estimated genetic and phenotypic correlations between milking speed and dairy traits were low, positive for yields and negative for contents. Segregation analysis yielded a highly significant likelihood ratio, confirming the segregation of a major gene with two alleles with partial dominance. The difference between the mean values of the two homozygotes was around 2.3 phenotypic standard deviation units of the trait. The major gene explained more than 60% of the estimated total genetic variance. The estimate of the 'residual' heritability, after taking into account the effect of the major locus, was 0.30.

Animals↗
PubMed2003

Multivariate mixed inheritance models for QTL detection on porcine chromosome 6.

A series of multivariate mixed-inheritance models is fitted to the data from an outbred-line pig cross commercially used in Norway. Each model accommodates information on polygenic (co)variances between F2 individuals and their F1 parents across the five traits through incorporation of a random animal effect. Considered traits relate to meat quality and are chosen following up the results from a previous evaluation, in which a putative quantitative trait locus (QTL) was identified on chromosome six that affects the amount of intramuscular fat (IMF), meat percentage, meat tenderness and smell intensity (Grindflek et al., 2001). An additional trait included in the model, based on results of other studies, is the backfat thickness. The analysed material comprises data scored for 305 F2 individuals, whereas marker information is available for F1 and F2 generations. Based on the results of the multivariate analysis with the mixed-inheritance model, it was possible to conclude that the evidence for QTLs for meat percentage, meat tenderness and smell intensity in the study of Grindflek et al. (2001) do not represent separate QTLs, but is caused by the fact that the applied pre-adjustment of trait values for polygenic effects failed properly to remove the polygenic variation. The QTL effect on IMF on chromosome six was confirmed.

Animals↗
PubMed1999

Spontaneous combined hyperlipidemia, coronary heart disease and decreased survival in Dahl salt-sensitive hypertensive rats transgenic for human cholesteryl ester transfer protein.

The acceleration of atherosclerosis by polygenic (essential) hypertension is well-characterized in humans; however, the lack of an animal model that simulates human disease hinders the elucidation of pathogenic mechanisms. We report here a transgenic atherosclerosis-polygenic hypertension model in Dahl salt-sensitive hypertensive rats that overexpress the human cholesteryl ester transfer protein (Tg[hCETP]DS). Male Tg[hCETP]DS rats fed regular rat chow showed age-dependent severe combined hyperlipidemia, atherosclerotic lesions, myocardial infarctions and decreased survival. These findings differ from various mouse atherosclerosis models, demonstrating the necessity of complex disease modeling in different species. The data demonstrate that cholesteryl ester transfer protein can be proatherogenic. The interaction of polygenic hypertension and hyperlipidemia in the pathogenesis of atherosclerosis in Tg[hCETP]DS rats substantiates epidemiological observations in humans.

Animals↗
PubMed1975

A test of the influence of isoallelic variation upon a quantitative character.

In order to test the assumption that isoalleles can contribute to polygenic variation, several isoalleles of cubitus interruptus were examined for their influence upon the quantitative expression of a related venation mutant, veinlet. In spite of the fact that veinlet and cubitus interruptus affect closely related developmental processes, the ci isoalleles had no effect upon the expression of veinlet. This test does not, of course, disprove the hypothesis that isoalleles play a part in polygenic variation. It is clear, however, that not all seemingly relevant isoalleles are necessarily effective elements in a given polygenic system.

Alleles↗
PubMed1992

Methods of segregation analysis for animal breeding data: a comparison of power.

Maximum likelihood segregation analysis provides potentially the most powerful method for the detection of segregating major genes. Segregation analysis requires the comparison of the likelihood of the data under the combined model (allowing both polygenic and major gene genetic variation) with the likelihood of the data under the polygenic model (allowing only polygenic genetic variation). In this study three approximations to the combined model likelihood were compared using simulated data, both with and without a segregating major gene, containing observations on paternal half-sibs. The use of Hermite integration to replace the integration in the combined model likelihood provided the most powerful test for a major gene. Two approximations, based on extensions of linear-mixed-model theory and estimating transmitting abilities for sires, were also considered. These approximations were less powerful than the use of Hermite integration, although the approximation estimating a transmitting ability for each major genotype for the sires was an improvement over the approximation estimating a single transmitting ability. For each approximation the frequency of detection of a major gene depended on the proportion of the genetic variance explained by the simulated major gene and whether the major gene caused the distribution to be skewed.

Alleles↗
PubMed2026

Genetics of major depressive disorder in a homogeneous population with uniform phenotyping.

Harmonized phenotyping and diverse population-specific studies are crucial for advancing gene discovery in psychiatric genetics. We conducted a genome-wide association (GWAS) mega-analysis of DSM-defined lifetime major depressive disorder (MDD) in 64 941 participants (25.7% cases) from the Dutch BIObanks Netherlands Internet Collaboration (BIONIC) consortium. Liability-scale SNP-based heritability was 12.0% (SE = 1.4%) as estimated by LDSC (assuming a lifetime prevalence of 15%) and 26.6% (SE = 1.1%) when estimated by LDAK-REML on individual-level genotype data, indicating substantial common-variant signal in this clinically harmonized sample. The genetic correlation with the latest major depression GWAS from the Psychiatric Genomics Consortium (PGC-MD) was high (rG = 0.89, SE = 0.048). Polygenic scores (PGSs) based on BIONIC predicted depression in UK Biobank, and PGSs derived from PGC-MD predicted MDD in BIONIC, supporting transferability of depression polygenic signal across cohorts and phenotype definitions. Within-family PGS analyses in twins suggested that the observed prediction was not primarily driven by detectable family-level confounding, and twin concordance for MDD increased with polygenic burden. We identified one genome-wide significant locus, indexed by rs3818852 in PALMD, but this finding currently lacks independent replication and should be interpreted cautiously. Finally, genetic correlation and latent causal variable analyses identified multiple traits showing shared or directionally consistent genetic associations with MDD. Together, these findings underscore the value of clinically harmonized phenotyping in regional biobank collaborations for studying the genetic architecture of MDD.

Humans↗
PubMed2026

Distinguishing different psychiatric disorders using DDx-PRS.

Despite great progress on case-control polygenic prediction, an unmet need remains for a method that genetically distinguishes clinically related disorders (e.g., schizophrenia (SCZ) versus bipolar disorder (BIP) versus major depressive disorder (MDD) versus controls). We introduce differential diagnosis-polygenic risk score (DDx-PRS), which jointly estimates the posterior probabilities of each diagnostic category (e.g., SCZ = 50%, BIP = 25%, MDD = 15%, control = 10%) by modeling variance-covariance structure across disorders, leveraging case-control polygenic risk scores and prior clinical probabilities for each diagnostic category. We applied DDx-PRS to Psychiatric Genomics Consortium SCZ, BIP, MDD and control data, including summary-level training data from three case-control genome-wide association studies (n = 41,917-173,140 cases; total n = 1,048,683) and held-out test data from different cohorts with equal numbers for each diagnostic category (total n = 11,460). DDx-PRS was well calibrated and well powered (consistent with simulations) and produced comparable results to methods that require tuning data. True diagnosis probabilities in the top deciles of predicted diagnosis probabilities were considerably larger than prior baseline probabilities, implying appreciable potential for clinical utility in certain settings.

Humans↗
PubMed2002

An evaluation of the variance components approach: type I error, power and size of the estimated effect.

In order to evaluate the statistical properties of the variance components method implemented in SOLAR and GENEHUNTER2, the type I error rate, power and estimated size of modelled effects were determined using computer simulation. Results suggested that the type I error rate was quite conservative when the variance was completely due to random effects. However, when either a polygenic effect or an unlinked single locus component effect was included in the generating models the type I error rate was closer to the nominal level. The size of the polygenic or single locus effect appeared to influence the type I error rate. Results suggested that the variance components method underestimated the variance attributed to a single locus effect and overestimated the variance attributed to a polygenic effect in the models considered regardless of the source of variation.

Analysis of Variance↗
PubMed2004

An indication of major genes affecting hip and elbow dysplasia in four Finnish dog populations.

The aim of the study was to assess the possible existence of major genes influencing hip and elbow dysplasia in four dog populations. A Bayesian segregation analysis was performed separately on each population. In total, 34 140 dogs were included in the data set. Data were analysed with both a polygenic and a mixed inheritance model. Polygenic models included fixed and random environmental effects and additive genetic effects. To apply mixed inheritance models, the effect of a major gene was added to the polygenic models. The major gene was modelled as an autosomal biallelic locus with Mendelian transmission probabilities. Gibbs sampling and a Monte Carlo Markov Chain algorithm were used. The goodness-of-fit of the different models were compared using the residual sum-of-squares. The existence of a major gene was considered likely for hip dysplasia in all the breeds and for elbow dysplasia in one breed. Several procedures were followed to exclude the possible false detection of major genes based on non-normality of data: permuted datasets were analysed, data-transformations were applied, and residuals were judged for normality. Allelic effects at the major gene locus showed nearly to complete dominance, with a recessive, unfavourable allele in both traits. Relatively high estimates of the frequencies of unfavourable alleles in each breed suggest that considerable genetic progress would be possible by selection against major genes. However, the major genes that are possibly affecting hip and elbow dysplasia in these populations will require further study.

Alleles↗
PubMed1998

Hypothalamic expression of neuropeptide-Y in the New Zealand obese mouse.

OBJECTIVE: Increased levels of hypothalamic neuropeptide-Y (NPY) are thought to contribute to the manifestation of the obese phenotype. The aim of this study was to characterize the interactions between leptin, insulin and NPY in the pathogenesis of polygenic obesity. DESIGN AND METHODS: A polygenic obese animal model, the New Zealand obese mouse (NZO) and its age-matched control, was used to assess the hypothalamic mRNA expression of NPY, the insulin receptor (IR) and the leptin receptor (Ob-Rb), by semiquantitative polymerase chain reaction. Experiments were performed early (at eight weeks old) and late (at 40 weeks old) in the life of these animals. RESULTS: Serum glucose was significantly elevated in obese mice. Serum insulin levels were not different between obese and lean mice, whereas serum leptin levels were significantly elevated in obese mice and increased continuously during life [reaching extremely high values at 40 weeks (41.5+/-4.1 vs 3.4+/-0.25 ng/ml for obese and lean, respectively). The hypothalamic expression of NPY mRNA was significantly higher in NZO mice compared to controls at both eight weeks (2.3-fold) and 40 weeks (1.9-fold), respectively, whereas expression of IR and Ob-Rb remained unaffected. CONCLUSION: Increased hypothalamic expression of NPY due to leptin resistance, may be involved in the development of polygenic obesity. Unchanged Ob-Rb expression suggests that either a defective hypothalamic uptake or defects in Ob-Rb signalling underly this process.

Aging↗
PubMed2005

Recurring challenges from a necrotrophic fungal plant pathogen: a case study with Leptosphaeria maculans (causal agent of blackleg disease in brassicas) in Western Australia.

BACKGROUND: Blackleg disease of Brassica napus, caused by the necrotrophic fungus Leptosphaeria maculans, causes severe yield losses in Australia, Europe and Canada. In Western Australia, it nearly destroyed the oilseed rape industry in 1972 when host genotypes and conducive environmental conditions favoured severe epidemics. The introduction of cultivars with polygenic resistance and the adoption of sound cultural practices two decades later helped to manage the disease. These were abandoned by many farmers in recent years in favour of the effective but ephemeral resistance conferred by the single dominant gene-based resistance derived from B. rapa ssp. sylvestris. Recently, several cultivars carrying this gene have collapsed widely within a period of 3 years after their commercial release. An environment conducive to the disease and the association of the pathogen with susceptible hosts in Western Australia for over 80 years together have led to the proliferation of L. maculans races, amounting to half of all races delineated to date from Europe, including the United Kingdom, Canada and Australia. SCOPE: This review demonstrates the problems that emerge when traditional cultural practices employed, along with cultivars containing polygenic resistance to a serious necrotrophic pathogen, are discarded in preference to the exclusive deployment of effective but ephemeral single dominant gene-based resistance to the disease across Southern Australia. CONCLUSIONS: Single dominant gene-based resistance currently available, on its own, will not confer durable resistance to blackleg disease in oilseed rape. Return to earlier management practices, including reliance upon polygenic resistance and induced resistance, may be the best currently available options to maintain production in regions across Southern Australia predisposed to severe epidemics.

Ascomycota↗
PubMed2005

Conditional likelihood score functions for mixed models in linkage analysis.

In this paper, we develop a general strategy for linkage analysis, applicable for arbitrary pedigree structures and genetic models with one major gene, polygenes and shared environmental effects. Extending work of Whittemore (1996), McPeek (1999) and Hossjer (2003d), the efficient score statistic is computed from a conditional likelihood of marker data given phenotypes. The resulting semiparametric linkage analysis is very similar to nonparametric linkage based on affected individuals. The efficient score S depends not only on identical-by-descent sharing and phenotypes, but also on a few parameters chosen by the user. We focus on (1) weak penetrance models, where the major gene has a small effect and (2) rare disease models, where the major gene has a possibly strong effect but the disease causing allele is rare. We illustrate our results for a large class of genetic models with a multivariate Gaussian liability. This class incorporates one major gene, polygenes and shared environmental effects in the liability, and allows e.g. binary, Gaussian, Poisson distributed and life-length phenotypes. A detailed simulation study is conducted for Gaussian phenotypes. The performance of the two optimal score functions S(wpairs) and S(normdom) are investigated. The conclusion is that (i) inclusion of polygenic effects into the score function increases overall performance for a wide range of genetic models and (ii) score functions based on the rare disease assumption are slightly more powerful.

Alleles↗