Estimation of environmental and genetic components of quantitative traits with application to serum cholesterol levels.

A mixed model of environmental, polygenic, and major locus effects is developed, allowing for environmental correlations between first-degree relatives and spouses. Maximum-likelihood techniques are used to determine the relative contributions of each of these effects to a quantitative trait. Inclusion of a nuclear family in the sample is assumed to depend on the value of the quantitative trait of one member of the family, so conditional distributions are used. Application of the method to serum cholesterol data from the general population shows that the addition of a polygenic effect to a model that assumes only an environmental effect makes a significant improvement. A completely dominant single gene is also found to be influencing serum cholesterol levels. Although cholesterol levels have been adjusted for a range of factors, such as age, sex, weight/height, and marital status, environmental factors still account for about half the variability in the residual values.     

Multifactorial genetic models for quantitative traits in humans.

Quantitative traits measured in human families can be analyzed to partition the total population variance into genetic and environmental components, or to elucidate the genetic mechanism involved. We review the estimation of variance components directly from human pedigree data, or in the form of path coefficients from correlations between pairs of relatives. To elucidate genetic mechanisms, a mixed model that allows for segregation at a major locus, a polygenic effect and a sibling environmental correlation is described for nuclear families. In each case appropriate likelihoods are derived as a basis, using numerical maximum likelihood methods, for parameter estimation and hypothesis testing. A general model is then described that allows for several familial sources of environmental variation, assortative mating, and both major gene and polygenic effects; and an algorithm for calculating the likelihood of a pedigree under this model is indicated. Finally, some of the remaining problems in this area of biometric analysis are pointed out.     

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.     

Fluctuating asymmetry as a possible measure of developmental homeostasis in humans: a review

We investigate three hypotheses related to fluctuating asymmetry (FA) of bilateral morphologic traits in humans: (1) the magnitude of FA in individual suffering from different levels of morbidity is significantly elevated compared with FA in healthy control subjects, (2) FA is negatively correlated with an individual's heterozygosity, and (3) phenotypic variance of FA may have a significant genetic component (or at least a family resemblance). Our experimental data and the literature support the first hypothesis and indicate that individuals who suffer from chromosomal or polygenic morbidity and from anomalies or conditions of development with still unknown genetic components demonstrate an elevated FA of various structures. The literature regarding the second hypothesis is sparse but is generally in agreement with it, although some exceptions exist. A study of correlations of phenotypic scores of FA between family members of nuclear families in two independent samples has shown that FA variance in individual traits probably does not have any significant genetic component. However, phenotypic variance of the mean estimate of FA over 8 traits showed significant additive and nonadditive (dominance) genetic components, each about 0.30.     

A polygenic hypothesis for sex determination in the European sea bass Dicentrarchus labrax

Polygenic sex determination, although suspected in several species, is thought to be evolutionarily unstable and has been proven in very few cases. In the European sea bass, temperature is known to influence the sex ratio. We set up a factorial mating, producing 5.893 individuals from 253 full-sib families, all reared in a single batch to avoid any between-families environmental effects. The proportion of females in the offspring was 18.3%, with a large variation between families. Interpreting sex as a threshold trait, the heritability estimate was 0.62 +/- 0.12. The observed distribution of family sex ratios was in accordance with a polygenic model or with a four-sex-factors system with environmental variance and could not be explained by any genetic model without environmental variance. We showed that there was a positive genetic correlation between weight and sex (r(A) = 0.50 +/- 0.09), apart from the phenotypic sex dimorphism in favor of females. This supports the hypothesis that a minimum size is required for sea bass juveniles to differentiate as females. An evolution of sex ratio by frequency-dependent selection is expected during the domestication process of Dicentrarchus labrax populations, raising concern about the release of such fish in the wild.     

Familial resemblances in blood leukocyte DNA methylation levels

Epigenetic factors such as DNA methylation are DNA alterations affecting gene expression that can convey environmental information through generations. Only a few studies have demonstrated epigenetic inheritance in humans. Our objective is to quantify genetic and common environmental determinants of familial resemblances in DNA methylation levels, using a family based sample. DNA methylation was measured in 48 French Canadians from 16 families as part of the GENERATION Study. We used the Illumina HumanMethylation450 BeadChip array to measure DNA methylation levels in blood leukocytes on 485,577 CpG sites. Heritability was assessed using the variance components method implemented in the QTDT software, which partitions the variance into polygenic (G), common environmental (C), and non-shared environmental (E) effects. We computed maximal heritability, genetic heritability, and common environmental effect for all probes (12.7%, 8.2%, and 4.5%, respectively) and for statistically significant probes (81.8%, 26.9%, and 54.9%, respectively). Higher maximal heritability was observed in the Major Histocompatibility Complex region on chromosome 6. In conclusion, familial resemblances in DNA methylation levels are mainly attributable to genetic factors when considering the average across the genome, but common environmental effect plays an important role when considering statistically significant probes. Further epigenome-wide studies on larger samples combined with genome-wide genotyping studies are needed to better understand the underlying mechanisms of DNA methylation heritability.     

Multigenerational response to artificial selection for biased clutch sex ratios in Tigriopus californicus populations

Polygenic sex determination (PSD) is relatively rare and theoretically evolutionary unstable, yet has been reported across a range of taxa. Evidence for multilocus PSD is provided by (i) large between‐family variance in sex ratio, (ii) paternal and maternal effects on family sex ratio and (iii) response to selection for family sex ratio. This study tests the polygenic hypothesis of sex determination in the harpacticoid copepod Tigriopus californicus using the criterion of response to selection. We report the first multigenerational quantitative evidence that clutch sex ratio responds to artificial selection in both directions (selection for male‐ and female‐biased families) and in multiple populations of T. californicus. In the five of six lines that showed a response to selection, realized heritability estimated by multigenerational analysis ranged from 0.24 to 0.58. Divergence of clutch sex ratio between selection lines is rapid, with response to selection detectable within the first four generations of selection.     

Semiparametric variance components models for genetic studies with longitudinal phenotypes

In a family-based genetic study such as the Framingham Heart Study (FHS), longitudinal trait measurements are recorded on subjects collected from families. Observations on subjects from the same family are correlated due to shared genetic composition or environmental factors such as diet. The data have a 3-level structure with measurements nested in subjects and subjects nested in families. We propose a semiparametric variance components model to describe phenotype observed at a time point as the sum of a nonparametric population mean function, a nonparametric random quantitative trait locus (QTL) effect, a shared environmental effect, a residual random polygenic effect and measurement error. One feature of the model is that we do not assume a parametric functional form of the age-dependent QTL effect, and we use penalized spline-based method to fit the model. We obtain nonparametric estimation of the QTL heritability defined as the ratio of the QTL variance to the total phenotypic variance. We use simulation studies to investigate performance of the proposed methods and apply these methods to the FHS systolic blood pressure data to estimate age-specific QTL effect at 62cM on chromosome 17.     

Estimation of heritability from limited family data using genome-wide identity-by-descent sharing

Background

In classical pedigree-based analysis, additive genetic variance is estimated from between-family variation, which requires the existence of larger phenotyped and pedigreed populations involving numerous families (parents). However, estimation is often complicated by confounding of genetic and environmental family effects, with the latter typically occurring among full-sibs. For this reason, genetic variance is often inferred based on covariance among more distant relatives, which reduces the power of the analysis. This simulation study shows that genome-wide identity-by-descent sharing among close relatives can be used to quantify additive genetic variance solely from within-family variation using data on extremely small family samples.

Methods

Identity-by-descent relationships among full-sibs were simulated assuming a genome size similar to that of humans (effective number of loci ~80). Genetic variance was estimated from phenotypic data assuming that genomic identity-by-descent relationships could be accurately re-created using information from genome-wide markers. The results were compared with standard pedigree-based genetic analysis.

Results

For a polygenic trait and a given number of phenotypes, the most accurate estimates of genetic variance were based on data from a single large full-sib family only. Compared with classical pedigree-based analysis, the proposed method is more robust to selection among parents and for confounding of environmental and genetic effects. Furthermore, in some cases, satisfactory results can be achieved even with less ideal data structures, i.e., for selectively genotyped data and for traits for which the genetic variance is largely under the control of a few major genes.

Conclusions

Estimation of genetic variance using genomic identity-by-descent relationships is especially useful for studies aiming at estimating additive genetic variance of highly fecund species, using data from small populations with limited pedigree information and/or few available parents, i.e., parents originating from non-pedigreed or even wild populations.     

SPONTANEOUS MUTATIONS FOR LIFE-HISTORY CHARACTERS IN AN OBLIGATE PARTHENOGEN

By allowing mutations to accumulate spontaneously in different lines derived from a single female of an obligately parthenogenetic Daphnia, it has become possible to estimate the rate at which new genetic variance for life-history characters arises as well as to identify the average pleiotropic effects of mutant polygenes. The estimated polygenic mutation rates are quite compatible with those available for sexual organisms. The results are therefore in conflict with the hypothesis that parthenogens compensate for the loss of recombination by elevating the mutation rate. Based on these results, it is argued that the rate of phenotypic evolution may be enhanced as much as five-fold by sexuality. However, if dominance or epistatic gene interactions are of major importance, or if the sensitivity to environmental effects is reduced or the rate of polygenic mutation enhanced under asexuality, the full advantage of sex will not be attained and may even be reversed. Regardless of these conditions, it is clear that the mutational rate of production of polygenic variation is sufficient to allow significant rates of phenotypic evolution in purely asexual organisms.     

Familial Clustering of Abdominal Visceral Fat and Total Fat Mass: The Québec Family Study

The evidence for common familial factors underlying total fat mass (estimated from underwater weighing) and abdominal visceral fat (assessed from CT scan) was examined in families participating in phase 2 of the Québec Family Study (QFS) using a bivariate familial correlation model. Previous QFS investigations suggest that both genetic (major and polygenic) and familial environmental factors influence each phenotype, accounting for between 55% to 71% of the phenotypic variance in fat mass, and between 55% to 72% for abdominal visceral fat The current study suggests that the bivariate familial effect ranges from 29% to 50%. This pattern suggests that there may be common familial determinants for abdominal visceral fat and total fat mass, as well as additional familial factors which are specific to each. The relatively high spouse cross-trait correlations usually suggest that a large percent of the bivariate familial effect may be environmental in origin. However, if mating is not random, then the spouse resemblance may reflect either genetic or environmental causes, depending on the source [i.e., through similar genes or cohabitation (environmental) effects]. Finally, there are significant sex differences in the magnitude of the familial cross-trait correlations involving parents, but not offspring, suggesting complex generation (i.e., age) and sex effects. For example, genes may turn on or off as a function of age and sex, and/or there may be an accumulation over time of effects due to the environment which may vary by sex. Whether the common familial factors are genetic (major and/or polygenic), environmental, or some combination of both, and whether the familial expression depends on sex and/or age warrants further investigation using more complex models.     

Polygenic and socioeconomic risk for high body mass index: 69 years of follow-up across life

Genetic influences on body mass index (BMI) appear to markedly differ across life, yet existing research is equivocal and limited by a paucity of life course data. We thus used a birth cohort study to investigate differences in association and explained variance in polygenic risk for high BMI across infancy to old age (2–69 years). A secondary aim was to investigate how the association between BMI and a key purported environmental determinant (childhood socioeconomic position) differed across life, and whether this operated independently and/or multiplicatively of genetic influences. Data were from up to 2677 participants in the MRC National Survey of Health and Development, with measured BMI at 12 timepoints from 2–69 years. We used multiple polygenic indices from GWAS of adult and childhood BMI, and investigated their associations with BMI at each age. For polygenic liability to higher adult BMI, the trajectories of effect size (β) and explained variance (R²) diverged: explained variance peaked in early adulthood and plateaued thereafter, while absolute effect sizes increased throughout adulthood. For polygenic liability to higher childhood BMI, explained variance was largest in adolescence and early adulthood; effect sizes were marginally smaller in absolute terms from adolescence to adulthood. All polygenic indices were related to higher variation in BMI; quantile regression analyses showed that effect sizes were sizably larger at the upper end of the BMI distribution. Socioeconomic and polygenic risk for higher BMI across life appear to operate additively; we found little evidence of interaction. Our findings highlight the likely independent influences of polygenic and socioeconomic factors on BMI across life. Despite sizable associations, the BMI variance explained by each plateaued or declined across adulthood while BMI variance itself increased. This is suggestive of the increasing importance of chance (‘non-shared’) environmental influences on BMI across life.     

Genetic evaluation with data presenting evidence of mixed major gene and polygenic inheritance

Summary A procedure for genetic evaluation with field data is proposed for situations in which there is mixed major gene and polygenic inheritance and the major genotype membership of some or of all individuals is unknown. Location parameters (fixed environmental, major genotype and polygenic effects), major genotype frequencies and variance components are estimated by the modal values of joint and marginal posterior distributions. The method is described for continuous and discontinuous data as well as for univariate and multivariate evaluations. Results from a simulation study are presented.Journal Paper No. J-12728 of the Iowa Agriculture and Home Economics Experiment Station, Ames, Iowa. Project No. 1901     

Inheritance of acute appendicitis: familial aggregation and evidence of polygenic transmission.

We explored familiality as well as the heritability and possible mode(s) of inheritance of acute appendicitis in childhood and early adolescence. Our case-control study showed that a positive family history for reported appendectomy was significantly more frequent in families of 80 consecutive patients eventually proved to have histopathologic acute appendicitis than in families of surgical controls matched for sex, age, and number of siblings. The relative risk was 10.0 (95% confidence limits 4.7-21.4). The pattern of familial aggregation was further supported by the fact that the age-standardized morbidity ratio was four times greater among family members of cases than among controls. We then applied the unified mixed model of segregation analysis, as implemented in the computer program POINTER, to a new set of 100 multigenerational pedigrees of children with histopathologically confirmed acute appendicitis that were broken down into 674 nuclear families. Age-specific morbidity risk and lifetime incidence of acute appendicitis were estimated from relatives of controls matched for age and sex to probands. Complex segregation analysis supported a polygenic or multifactorial model with a total heritability of 56%. There was no evidence to support a major gene, although a rare gene could not be ruled out as the cause of a small proportion of cases. Specific studies to address genetic and environmental factors in this serious disease seem worthwhile; but, for now, a positive family history of appendicitis might join other evidence leading to improved clinical recognition of acute appendicitis.     

PATERNAL EFFECTS IN INHERITANCE OF A PATHOGEN RESISTANCE TRAIT IN IPOMOEA PURPUREA

For continuously variable, polygenic characters, the response to selection depends upon the proportion of phenotypic variance that is caused by additive genetic variance, or narrow-sense heritability. Thus, a major goal of quantitative genetics is to partition phenotypic variance for a trait in a way that isolates additive genetic variance from other causes. The variance among paternal half-sib families, which is frequently used to estimate additive variance, is commonly recognized to include additive epistatic effects. However, this variance component can also include non-Mendelian paternal effects. We report here the results from a diallel crossing design used to isolate nonnuclear effects from the paternal nuclear contribution to disease resistance in the common morning glory, Ipomoea purpurea. In particular, we found that genetic variance for resistance to anthracnose, a disease caused by the fungal pathogen Colletotrichum dematium, was determined largely by a nonnuclear, additive paternal effect. We discuss potential mechanisms for this effect as well as some of their evolutionary implications.     

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.