Additive Polygenic Model Research Articles

Common maternal and fetal genetic variants show expected polygenic effects on risk of small- or large-for-gestational-age (SGA or LGA), except in the smallest 3% of babies.

Babies born clinically Small- or Large-for-Gestational-Age (SGA or LGA; sex- and gestational age-adjusted birth weight (BW) <10th or >90th percentile, respectively), are at higher risks of complications. SGA and LGA include babies who have experienced environment-related growth-restriction or overgrowth, respectively, and babies who are heritably small or large. However, the relative proportions within each group are unclear. We assessed the extent to which common genetic variants underlying variation in birth weight influence the probability of being SGA or LGA. We calculated independent fetal and maternal genetic scores (GS) for BW in 11,951 babies and 5,182 mothers. These scores capture the direct fetal and indirect maternal (via intrauterine environment) genetic contributions to BW, respectively. We also calculated maternal fasting glucose (FG) and systolic blood pressure (SBP) GS. We tested associations between each GS and probability of SGA or LGA. For the BW GS, we used simulations to assess evidence of deviation from an expected polygenic model.Higher BW GS were strongly associated with lower odds of SGA and higher odds of LGA (ORfetal = 0.75 (0.71,0.80) and 1.32 (1.26,1.39); ORmaternal = 0.81 (0.75,0.88) and 1.17 (1.09,1.25), respectively per 1 decile higher GS). We found evidence that the smallest 3% of babies had a higher BW GS, on average, than expected from their observed birth weight (assuming an additive polygenic model: Pfetal = 0.014, Pmaternal = 0.062). Higher maternal SBP GS was associated with higher odds of SGA P = 0.005.We conclude that common genetic variants contribute to risk of SGA and LGA, but that additional factors become more important for risk of SGA in the smallest 3% of babies.

The Relevance of Variants With Unknown Significance for Autism Spectrum Disorder Considering the Genotype-Phenotype Interrelationship.

Several efforts in basic and clinical research have been contributing to unveiling the genetics behind autism spectrum disorders (ASD). However, despite these advancements, many individuals diagnosed with ASD and related neuropsychiatric conditions have been genetically investigated without elucidative results. The enormous genetic complexity of ASD-related conditions makes it a significant challenge to achieve, with a growing number of genes (close to a thousand) involved, belonging to different molecular pathways and presenting distinct genetic variations. Next-generation sequencing (NGS) is the approach most used in genetic research related to ASD, identifying de novo mutation, which is closely related to more severe clinical phenotypes, especially when they affect constrained and loss-of-function intolerant genes. On the other hand, de novo mutation findings contribute to a small percentage of the ASD population, since most of the cases and genetic variants associated with neuropsychiatric conditions are inherited and phenotypes are results of additive polygenic models, which makes statistical efforts more difficult. As a result, NGS investigation can sound vainly or unsuccessful, and new mutations on genes already related with ASD are classified as variants of unknown significance (VUS), hampering their endorsement to a clinical phenotype. This review is focused on currently available strategies to clarify the impact of VUS and to describe the efforts to identify more pieces of evidence throughout clinical interpretation and genetic curation process.

Genetic Architecture of Domestication-Related Traits in Maize

Strong directional selection occurred during the domestication of maize from its wild ancestor teosinte, reducing its genetic diversity, particularly at genes controlling domestication-related traits. Nevertheless, variability for some domestication-related traits is maintained in maize. The genetic basis of this could be sequence variation at the same key genes controlling maize-teosinte differentiation (due to lack of fixation or arising as new mutations after domestication), distinct loci with large effects, or polygenic background variation. Previous studies permit annotation of maize genome regions associated with the major differences between maize and teosinte or that exhibit population genetic signals of selection during either domestication or postdomestication improvement. Genome-wide association studies and genetic variance partitioning analyses were performed in two diverse maize inbred line panels to compare the phenotypic effects and variances of sequence polymorphisms in regions involved in domestication and improvement to the rest of the genome. Additive polygenic models explained most of the genotypic variation for domestication-related traits; no large-effect loci were detected for any trait. Most trait variance was associated with background genomic regions lacking previous evidence for involvement in domestication. Improvement sweep regions were associated with more trait variation than expected based on the proportion of the genome they represent. Selection during domestication eliminated large-effect genetic variants that would revert maize toward a teosinte type. Small-effect polygenic variants (enriched in the improvement sweep regions of the genome) are responsible for most of the standing variation for domestication-related traits in maize.

Relative performance of gene- and pathway-level methods as secondary analyses for genome-wide association studies

BackgroundDespite the success of genome-wide association studies (GWAS), there still remains “missing heritability” for many traits. One contributing factor may be the result of examining one marker at a time as opposed to a group of markers that are biologically meaningful in aggregate. To address this problem, a variety of gene- and pathway-level methods have been developed to identify putative biologically relevant associations. A simulation was conducted to systematically assess the performance of these methods. Using genetic data from 4,500 individuals in the Wellcome Trust Case Control Consortium (WTCCC), case–control status was simulated based on an additive polygenic model. We evaluated gene-level methods based on their sensitivity, specificity, and proportion of false positives. Pathway-level methods were evaluated on the relationship between proportion of causal genes within the pathway and the strength of association.ResultsThe gene-level methods had low sensitivity (20-63%), high specificity (89-100%), and low proportion of false positives (0.1-6%). The gene-level program VEGAS using only the top 10% of associated single nucleotide polymorphisms (SNPs) within the gene had the highest sensitivity (28.6%) with less than 1% false positives. The performance of the pathway-level methods depended on their reliance upon asymptotic distributions or if significance was estimated in a competitive manner. The pathway-level programs GenGen, GSA-SNP and MAGENTA had the best performance while accounting for potential confounders.ConclusionsNovel genes and pathways can be identified using the gene and pathway-level methods. These methods may provide valuable insight into the “missing heritability” of traits and provide biological interpretations to GWAS findings.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0191-2) contains supplementary material, which is available to authorized users.

Retrospective Association Analysis of Binary Traits: Overcoming Some Limitations of the Additive Polygenic Model

Case-control genetic association analysis is an extremely common tool in human complex trait mapping. From a statistical point of view, the analysis of binary traits poses somewhat different challenges from the analysis of quantitative traits. Desirable features of a binary trait mapping approach would include (1) phenotype modeled as binary, with appropriate dependence between the mean and variance; (2) appropriate correction for relevant covariates; (3) appropriate correction for sample structure of various types, including related individuals, admixture and other types of population structure; (4) both fast and accurate computations; (5) robustness to ascertainment and other types of phenotype model misspecification, and (6) ability to leverage partially missing data to increase power. We review these challenges and argue, both theoretically and in simulations, for the value of retrospective association analysis as a way to overcome some of the limitations of the phenotype model, including model misspecification due to ascertainment. We give an overview of two recent retrospective methods, CARAT and CERAMIC, that are designed to meet criteria 1-6.

English

The effect of the fragile X allele on ridge breadth, height and testicular volume was examined using robust statistical techniques for the data collected from 8 families from Ibadan, south west Nigeria, afflicted with this disorder. There is the presence of outliers, an estimated 6.5% for testicular volume and 1.3% for ridge breadth and height data respectively. It is shown that fragile X affects ridge breadth, height and testicular volume in a different manner. Fragile X women had a greater mean ridge breadth than normal women; a pattern similar to normal and fragile X men but the differences were not significant. Fragile X men were shorter than normal men, but no significant difference between the mean height of normal and fragile X women was observed. Whereas fragile X girls were shown to grow more quickly and to stop growth earlier than normal girls, normal women were taller than fragile X women. Testicular volume in fragile X boys continue in development long after normal boys have stopped; an observation that could explain the significant difference in means of adult males. An examination of the covariance between relatives classified according to fragile X status showed that for the three traits the influence of fragile X alleles was to reduce the covariance between parents and offspring, the effect of which produces a departure from an additive polygenic model of inheritance. &nbsp; Key words: Fragile X allele, ridge breadth, testicular volume, single-gene disorder.

High Heritability but Uncertain Mode of Inheritance for Total Serum IgE Level andSchistosoma mansoniInfection Intensity in a Schistosomiasis‐Endemic Brazilian Population

Evidence of genetic control for total serum IgE (tIgE) level has been reported in multiple populations, although populations with substantial exposure to helminths have yielded lower estimates of heritability, despite evidence suggesting that genes also control a significant portion of the variation in the number of Schistosoma mansoni eggs per gram of fecal matter. By use of a whole-population ascertainment scheme, 822 individuals were enrolled from a schistosomiasis-endemic area in Conde, Bahia, in Brazil. Heritability was estimated by using an additive polygenic model, and segregation analysis was performed for 2 quantitative traits, tIgE level and egg count. After adjusting for nongenetic covariates, the heritability of log-transformed tIgE level and log-transformed egg count was estimated at 60% and 31%, respectively. No evidence for a single major gene controlling tIgE level or egg count was observed in segregation analysis for 781 individuals and 403 individuals, respectively, in 318 families, however, which suggests complex biological control. The high heritability of tIgE level indicates that genetic factors are likely to control tIgE level even in the presence of helminthic infection. Substantial heritability for the burden of S. mansoni infection was confirmed in these Brazilian families. Further genetic studies will be needed to dissect the specific genetic factors that underlie these traits.

Familial correlations and inter-relationships of four asthma-associated quantitative phenotypes in 320 French EGEA families ascertained through asthmatic probands.

Asthma is a complex disease, associated with biological and physiological phenotypes including immunoglobulin E (IgE) levels, sum of positive skin prick tests to allergens (SPTQ), eosinophil counts (EOS) and percent predicted forced expiratory volume in 1 s (%FEV1). We investigated the patterns of familial correlations and the inter-relationships of these four quantitative phenotypes, using the general class D regressive model, in 320 French EGEA nuclear families ascertained through 204 offspring (set A) and 116 parents (set B). Familial correlations of IgE and SPTQ were consistent with a model including no spouse correlation and equal parent-offspring and sib-sib correlations (rhoPO = rhoSS = 0.25 for IgE and 0.15 for SPTQ), this model being compatible with an additive polygenic model in the whole sample and the two family subsets A and B. Different patterns of familial correlations of EOS and %FEV1 were observed in these two sets. In set A, the best fitting model included no spouse correlation and equality of parent-offspring and sib-sib correlations (rhoPO = rhoSS = 0.14 for EOS and 0.23 for %FEV1). In set B, EOS had only a significant rhoSS of 0.28, while %FEV1 had significant rhoMO of 0.28 and rhoSS of 0.16. Analysis of shared familial determinants between these phenotypes indicated an overlap of at most 30% in rhoFO for IgE and SPTQ and in both rhoFO and rhoMO for IgE and EOS, while determinants of %FEV1 and atopy-related phenotypes appear distinct. These results may have implications for further linkage and association studies with genetic markers.

Evidence for additive polygenic control of pupation height in Drosophila ananassae.

In order to study the mode of inheritance of pupation height in Drosophila ananassae, two mass culture stocks derived from ecogeographically different localities in India, were used to make a complete set of 16 crosses, which include parentals, F1, backcrosses, and F2. Pupation height defined as the distance a larva pupates over the surface of culture medium was scored in all 16 crosses. The two parental lines showed significant difference in pupation height. The F1 larvae in both reciprocal crosses had intermediate pupation height and there was no difference between two reciprocal crosses as well as between F1 and mid parent value. However, there was greater variance in the F2 generation. These findings provide evidence that the inheritance of pupation height fits a classical additive polygenic model and suggested that there is substantial amount of additive genetic variation in natural populations of D. ananassae. Furthermore, the analysis of reciprocal backcrosses shows significant maternal effect. Progeny with low pupating mothers showed lower pupation height than those with low pupating fathers and progeny with high pupating mothers had higher pupation height than those with high pupating fathers. Since the maternal effect was found only in backcrosses but not in the F1, it is suggested that this maternal effect on pupation height follows the pattern of inheritance of a transient maternal effect.

Genetic and environmental influences on left ventricular mass. A family study.

The relations between left ventricular mass (LVM) with age, gender, body size, and blood pressure were investigated in healthy adults and children from 149 nuclear families. LVM was strongly correlated with overall weight, especially in the children. Genetic analysis indicated that the segregation of LVM was compatible with an additive polygenic model, with a heritability estimate of 34% before adjustment for weight and 28% after adjustment for weight. Genetic and/or familial environmental factors played a strong role in the correlation of LVM and weight; they accounted for all of the correlation between the 2 traits in adults and 59% of the correlation in children. Spouses exhibited a strong correlation in their weight, which suggested that common family environment may contribute to the family correlations and to the observed heritability of the trait. LVM was strongly correlated with blood pressure before adjustment for weight, but this correlation could be attributed to nonfamilial environment rather than genetic factors. After adjustment for weight, the intertrait correlations between LVM and blood pressure were nonsignificant. Thus, adjustment for weight accounts for all common determinants of LVM and blood pressure.

Convergence of Covariance Structures in Additive Gaussian Polygenic Models

The purpose of this paper is to present convergence results for covariance structures of allelic effects over successive generations in Gaussian polygenic models for quantitative traits developed by Lande (1976, Genetical Research 26, 221-235; 1977, Genetics 86, 485-498) and Chevalet (1988, in Proceedings of the Second International Conference on Quantitative Genetics, 379-394). The proofs rely on concavity properties of transformations of covariance matrices.

Use of robust statistical methods to determine the effect of fragile X on means and variance components of a quantitative trait

Owing to the presence of outliers, an estimated 3.5% in the ridge breadth data and 1.7% in the height data, the effect of fragile X on height and ridge breadth was examined using robust statistical techniques for data collected from 54 families afflicted with this disorder. It is shown that fragile X affects ridge breadth and height in a different manner. Fragile X women had a greater mean ridge breadth than normal women, whereas there was a similar trend, but no significant difference, between normal and fragile X men. Fragile X men were shorter than normal men, but no significant difference between the mean height of normal and fragile X women was observed. However, fragile X girls were shown to grow more quickly and to stop growing earlier than normal girls. An examination of the covariance between relatives classified according to fragile X status showed that for both traits the effect of fragile X was to reduce the covariance between parents and offspring, which produced the effect of departure from an additive polygenic model of inheritance.

Long-term effects of selection based on the animal model BLUP in a finite population

Monte Carlo simulation was used to assess the long-term effects of truncation selection within small populations using indices (I=ωf+m) combining mid-parent [f=(a i+a d)/2] and Mendelian-sampling (m=a-f) evaluations provided by an animal model BLUP (a=f+m). Phenotypic values of panmictic populations were generated for 30 discrete generations. Assuming a purely additive polygenic model, heritability (h 2) values were 0.10, 0.25 or 0.50. Two population sizes were considered: five males and 25 females selected out of 50 candidates of each sex (small populations, S) and 50 males and 250 females selected out of 500 candidates in each sex (large populations, L). Selection was carried out on the index defined above with ω = 1 (animal model BLUP), ω=1/2, or ω=0 (selection on within-family deviations). Mass selection was also considered. Selection based on the animal model BLUP (ω=1) maximized the cumulative genetic gain in L populations. In S populations, selection using ω = 1/2 and mass selection were more efficient than selection under an animal model (+ 3 to + 7% and + 1 to + 4% respectively, depending on h (2)). Selection on within-family deviations always led to the lowest gains. In most cases, the variance of response to selection between replicates did not depend on the selection method. The within-replicate genetic variance and the average coefficient of inbreeding (F) were highly affected by selection with ω=1 or 1/2, especially in populations of size S. As expected, selection based on within-family deviations was less detrimental in that respect. The number of copies of founder neutral genes at a separate locus, and the probability vector of origin of the genes in reference to the founder animals, were also observed in addition to F values. The conclusion was that selection procedures placing less emphasis on family information might be interesting alternatives to selection based on animal model BLUP, especially for small populations with long-term selection objectives.

Determining the Mode of Inheritance of Pesticide Resistance with Backcross Experiments

The most widely used method for evaluating the mode of inheritance of pesticide resistance is based on bioassays of individuals from a backcross between F1 (hybrid of resistant and susceptible strains) and parental resistant or susceptible strains. Monte Carlo simulations of the standard backcross method showed that the probability of incorrectly rejecting the null hypothesis of monogenic inheritance (Type I error) was generally more than double the conventional value of P = 0.05. Conversely, the null hypothesis of monogenic inheritance was likely to be accepted in a relatively large proportion of cases in which resistance is controlled by two or more loci. Expected differences in mortality of backcross offspring between monogenic and additive polygenic models approached zero as dose approached extremely low values, extremely high values, and the LD50 of the backcross generation. Thus, the effectiveness of the backcross method depended strongly on dose. The power of the standard backcross method to correctly reject the null hypothesis of monogenic inheritance increased as number of loci, slope of parental dose-mortality lines, magnitude of resistance, and sample size increased. Guidelines for improving the design and interpretation of backcross experiments are presented.

Predicting cumulated response to directional selection in finite panmictic populations

Accurate prediction of the cumulated genetic gain requires predicting genetic variance over time under the joint effects of selection and limited population size. An algorithm is proposed to quantify at each generation the effects of these factors on average coefficient of inbreeding, genetic variance, and genetic mean, under a purely additive polygenic model, with no mutation, and under the assumption of absence of inbreeding depression on viability affecting selection differentials. This algorithm is relevant to populations where mating is at random and generations do not overlap. It was tested via Monte Carlo simulation on a population of 3 males and 25 females mass selected out of 50 candidates of each sex, over 30 generations. For two values of the initial heritability of the selected trait, 0.5 and 0.9 (to represent high accuracy in index selection), predicted values of the genetic variance are in agreement with observed results up to the 12th and 19th generations, respectively. Beyond these generations, the variance is overestimated, due to an underestimation of the effect of selection on the rate of inbreeding. Finally, the algorithm provides predictions of the cumulated responses close to the observed values in both selected populations. It is concluded that, as regards the hypotheses of the study, the proposed algorithm is satisfactory, and could be used to optimize selection methods with respect to the cumulated genetic gain in the mid- or long-term. Possible extensions of the algorithm to more realistic situations are discussed.

Complex segregation analysis of dental morphological variants.

A set of 20 morphological variants of the dental crowns and four characteristics of the jaws are tested for probable mode of inheritance using the complex segregation analysis method of Morton et al. (Am. J. Hum. Genet. 23:602-611, 1971). Models tested include three two-allele single-locus models (dominant, codominant, and recessive) and a model employing the polychotomized normal distribution of liability (an additive polygenic model), with transmissibility estimated via maximum likelihood. Most of the traits studied are observed using ordinal scales with several grades, and many are tested using more than one dichotomy of their scale. These multiple analyses allow for an examination of such factors as trait incidence on the results of the statistical analysis. The results of the analysis yield propositions of major genes for 13 of the 24 traits examined. Two traits give good evidence of being polygenic in origin. The remaining nine characters present methodological problems that do not allow for a definite conclusion on their mode of inheritance at this time. The ability to test varying levels of transmissibility in the polygenic model allows for an estimation of the percentage of trait variance determined by familial factors. Estimates of transmissibility for all characters examined range from 0 to 1, with a mean of 0.36. These findings may suggest a large environmental role in the development of dental crown morphology. However, the possibility exists that difficulties in the ability to classify the expression of certain traits consistently result in overestimates of the environmental influences on the development of those characters.

A Diploid "Sexy Son" Model

The "sexy son" hypothesis proposes that female mating preferences have evolved in such a way that in a polygynous mating system some females preferentially mate with males having high attractiveness and low fertility. Kirkpatrick's (1985) analyses of haploid and additive polygenic models have discredited the sexy-son hypothesis, suggesting that neither the genetic disposition to become a sexy male nor the tendency to mate with them will normally increase under selection (except in a "runaway" process). Analysis of haploid models has also led to the claim that polymorphism of sexually selected traits and female mating preferences cannot be maintained at equilibrium. Here, we present results of a diploid sexy-son model, demonstrating by counterexample that generalizations from haploid and additive polygenic models are not valid. The diploid model allows trade-offs between fertility and sexual selection, stable polymorphisms for both male traits and female mating preferences, and increase of sexy males from low initial frequencies. The maximization principles derived from other models can be violated in the diploid case. The general problem of model sensitivity to ploidy and other genetic assumptions is discussed.

Autosomal and maternal effects on pupation behavior in Drosophila melanogaster.

This study demonstrates the importance of using a complete set of 16 reciprocal crosses (F1, backcrosses, and F2) to thoroughly investigate both genetic and nongenetic influences on patterns of inheritance of larval pupation behavior inDrosophila melanogaster. Larvae derived from natural populations show significant variation in pupal height, defined as the distance a larva pupates above the feeding substrate. Differences in the distance a larva pupates from fruit in nature is known to affect the fitness ofDrosophila populations. In this study the heredity of pupal height is analyzed by performing crosses between high- and low-pupating strains. We found that the inheritance of pupal height fit a classical additive polygenic model of inheritance, with intermediate F1 pupal heights and greater variances in the F2 generation. In addition, a significant maternal effect was also found by analyzing the reciprocal backcrosses. Progeny with low-pupating mothers had lower pupation heights than those with low-pupating fathers. Similarly, progeny with high-pupating mothers tended to have higher pupal heights than those with high-pupating fathers. This maternal effect was not attributable to strain differences in permanent cytoplasmic factors, sex chromosomes, or developmental time. Finally, we speculate upon the environmental conditions under which a transient maternal effect on pupation behavior would be expected to evolve in natural populations.

No evidence for sex-linked or sex-limited gene expression influencing spatial orientation.

Scores of 83 pairs of twins and their parents on the Cubes Comparison Test have been analyzed to test competing hypotheses about the origin of individual differences in spatial orientation. Models allowing for polygenic sex-linked or sex-limited gene expression show no improvement in fit over the simple autosomal additive polygenic model. However, individual environmental influences (E 1) account for twice as much variance in males as in females.

A genetic study of red blood cell zinc concentration in man.

Red blood cell zinc levels vary linearly with age within each sex. Age- and sex-adjusted zinc levels generated 6 familial correlations in nuclear families and twins. A simple additive polygenic model, with genetic heritability of zinc (h2) as the only unknown parameter, gave an excellent fit (X2(5) = 0.97, p greater than 0.96), with the corresponding estimate of h2 = 0.790 +/- 0.032. Commingling analysis supported the hypothesis that the logarithmic zinc values are approximately distributed according to a mixture of three normal distributions. Some support was found for a major gene hypothesis by complex segregation analysis under the mixed model. However, all the evidence came just from one family in which one of the 3 children's zinc value was over 3 standard deviations above the mean. When that family was excluded, there was no more evidence for a major gene. Under the most parsimonious mutlifactorial model that assumes equal heritabilities in children and adults, the heritability was estimated as 0.748 +/- 0.079, in good agreement with the outcome of path analysis. Biological interpretations are put forward and discussed.