The validity and heritability of self-report osteoarthritis in an Australian older twin sample.

In order to investigate the genetic and environmental antecedents of osteoarthritis (OA), self-report measures of joint pain, stiffness and swelling were obtained from a population-based sample of 1242 twin pairs over 50 years of age. In order to provide validation for these self-report measures, a subsample of 118 twin pairs were examined according to the American College of Rheumatology clinical and radiographic criteria for the classification of osteoarthritis. A variety of statistical methods were employed to identify the model derived from self-report variables which would provide optimal prediction of these standardised assessments, and structural equation modelling was used to determine the relative influences of genetic and environmental influences on the development of osteoarthritis. Significant genetic effects were found to contribute to osteoarthritis of the hands, hips and knees in women, with heritability estimates ranging from 30-46% depending on the site. In addition, the additive genetic effects contributing to osteoarthritis in various parts of the body were confirmed to be the same. Statistically significant familial aggregation of osteoarthritis in men was also observed, but it was not possible to determine whether this was due to genetic or shared environmental effects.     

Genetics of Callous-Unemotional Behavior in Children

Callous-unemotional behavior (CU) is currently under consideration as a subtyping index for conduct disorder diagnosis. Twin studies routinely estimate the heritability of CU as greater than 50%. It is now possible to estimate genetic influence using DNA alone from samples of unrelated individuals, not relying on the assumptions of the twin method. Here we use this new DNA method (implemented in a software package called Genome-wide Complex Trait Analysis, GCTA) for the first time to estimate genetic influence on CU. We also report the first genome-wide association (GWA) study of CU as a quantitative trait. We compare these DNA results to those from twin analyses using the same measure and the same community sample of 2,930 children rated by their teachers at ages 7, 9 and 12. GCTA estimates of heritability were near zero, even though twin analysis of CU in this sample confirmed the high heritability of CU reported in the literature, and even though GCTA estimates of heritability were substantial for cognitive and anthropological traits in this sample. No significant associations were found in GWA analysis, which, like GCTA, only detects additive effects of common DNA variants. The phrase ‘missing heritability’ was coined to refer to the gap between variance associated with DNA variants identified in GWA studies versus twin study heritability. However, GCTA heritability, not twin study heritability, is the ceiling for GWA studies because both GCTA and GWA are limited to the overall additive effects of common DNA variants, whereas twin studies are not. This GCTA ceiling is very low for CU in our study, despite its high twin study heritability estimate. The gap between GCTA and twin study heritabilities will make it challenging to identify genes responsible for the heritability of CU.     

Maximum likelihood estimation of human craniometric heritabilities

This study presents univariate narrow-sense heritability estimates for 33 common craniometric dimensions, calculated using the maximum likelihood variance components method on a skeletal sample of 298 pedigreed individuals from Hallstatt, Austria. Quantitative genetic studies that use skeletal cranial measurements as a basis for inferring microevolutionary processes in human populations usually employ heritability estimates to represent the genetic variance of the population. The heritabilities used are often problematic: most come from studies of living humans, and/or they were calculated using statistical techniques or assumptions violated by human groups. Most bilateral breadth measures in the current study show low heritability estimates, while cranial length and height measures have heritability values ranging between 0.102-0.729. There appear to be differences between the heritabilities calculated from crania and those from anthropometric studies of living humans, suggesting that the use of the latter in quantitative genetic models of skeletal data may be inappropriate. The univariate skeletal heritability estimates seem to group into distinct regions of the cranium, based on their relative values. The most salient group of measurements is for the midfacial/orbital region, with a number of measures showing heritabilities less than 0.30. Several possible reasons behind this pattern are examined. Given the fact that heritabilities calculated on one population should not be applied to others, suggestions are made for the use of the data presented.     

Combined genome scans for body stature in 6,602 European twins: evidence for common Caucasian loci

Twin cohorts provide a unique advantage for investigations of the role of genetics and environment in the etiology of variation in common complex traits by reducing the variance due to environment, age, and cohort differences. The GenomEUtwin (http://www.genomeutwin.org) consortium consists of eight twin cohorts (Australian, Danish, Dutch, Finnish, Italian, Norwegian, Swedish, and United Kingdom) with the total resource of hundreds of thousands of twin pairs. We performed quantitative trait locus (QTL) analysis of one of the most heritable human complex traits, adult stature (body height) using genome-wide scans performed for 3,817 families (8,450 individuals) derived from twin cohorts from Australia, Denmark, Finland, Netherlands, Sweden, and United Kingdom with an approximate ten-centimorgan microsatellite marker map. The marker maps for different studies differed and they were combined and related to the sequence positions using software developed by us, which is publicly available (https://apps.bioinfo.helsinki.fi/software/cartographer.aspx). Variance component linkage analysis was performed with age, sex, and country of origin as covariates. The covariate adjusted heritability was 81% for stature in the pooled dataset. We found evidence for a major QTL for human stature on 8q21.3 (multipoint logarithm of the odds 3.28), and suggestive evidence for loci on Chromosomes X, 7, and 20. Some evidence of sex heterogeneity was found, however, no obvious female-specific QTLs emerged. Several cohorts contributed to the identified loci, suggesting an evolutionarily old genetic variant having effects on stature in European-based populations. To facilitate the genetic studies of stature we have also set up a website that lists all stature genome scans published and their most significant loci (http://www.genomeutwin.org/stature_gene_map.htm).     

Stature estimation in prehistoric Native Americans of Ohio

In the present report we investigate stature estimation techniques in a sample of 64 (35 male, 29 female) prehistoric Native Americans from Ohio. Because living stature is unknown for these 64 individuals, we use Fully's (1956) anatomical method to provide the best estimates of living stature. In this method all osseous components of skeletal height are measured and soft tissue correction is added. Comparisons of regression equations commonly used for stature estimation in prehistoric Eastern Woodland Native American populations, but developed for East Asian and East Asian-derived populations (using lower extremity components), show that these commonly used equations consistently yield stature estimates 2 to 8 cm in excess of the best estimates from Fully's method. Based on the skeletal height measures of the 64 individuals in the present sample, we develop regression equations for the estimation of stature. These equations yield stature estimates virtually identical to estimates from Fully's method and may prove useful for stature reconstruction in other prehistoric Eastern Woodland Native American populations.     

Evidence for significant heritability of apoptotic and cell cycle responses to ionising radiation

Genetic factors are likely to affect individual cancer risk, but few quantitative estimates of heritability are available. Public health radiation protection policies do not in general take this potentially important source of variation in risk into account. Two surrogate cellular assays that relate to cancer susceptibility have been developed to gain an insight into the role of genetics in determining individual variation in radiosensitivity. These flow cytometric assays for apoptosis induction and cell cycle delay following radiation are sufficiently sensitive to distinguish lymphocytes from a healthy donor population from those of a sample of obligate carriers of ATM mutations (P = 0.01 and P = 0.02, respectively). Analysis of 54 unselected twin pairs (38 dizygotic, 16 monozygotic) indicated much greater intrapair correlation in response in monozygotic than in dizygotic pairs. Structural equation modelling indicated that models including unique environmental factors only fitted the data less well than those incorporating two or more of additive genetic factors, common environmental factors and unique environmental factors. A model incorporating additive genetic factors and unique environmental factors yielded estimates of heritability for the two traits of 68% (95% CI 40–82%, cell cycle) and 59% (95% CI 22–79%, apoptosis). Thus, these data suggest that genetic factors contribute significantly to human variation in these two measures of radiosensitivity that relate to cancer susceptibility.     

Heritability of adult body height: a comparative study of twin cohorts in eight countries.

A major component of variation in body height is due to genetic differences, but environmental factors have a substantial contributory effect. In this study we aimed to analyse whether the genetic architecture of body height varies between affluent western societies. We analysed twin data from eight countries comprising 30,111 complete twin pairs by using the univariate genetic model of the Mx statistical package. Body height and zygosity were self-reported in seven populations and measured directly in one population. We found that there was substantial variation in mean body height between countries; body height was least in Italy (177 cm in men and 163 cm in women) and greatest in the Netherlands (184 cm and 171 cm, respectively). In men there was no corresponding variation in heritability of body height, heritability estimates ranging from 0.87 to 0.93 in populations under an additive genes/unique environment (AE) model. Among women the heritability estimates were generally lower than among men with greater variation between countries, ranging from 0.68 to 0.84 when an additive genes/shared environment/unique environment (ACE) model was used. In four populations where an AE model fit equally well or better, heritability ranged from 0.89 to 0.93. This difference between the sexes was mainly due to the effect of the shared environmental component of variance, which appears to be more important among women than among men in our study populations. Our results indicate that, in general, there are only minor differences in the genetic architecture of height between affluent Caucasian populations, especially among men.     

学龄双生子儿童头面部特征的遗传学分析

为探讨遗传与环境因素对学龄双生子儿童头面部特征的影响, 对呼和浩特市和包头市7-12岁369对双生子儿童(同卵180对, 同性别异卵141对, 异性别异卵48对)的16项头面部指标进行活体测量。采用通径分析方法, 用Mx软件拟合最佳结构方程模型, 计算各指标遗传与环境方差组分, 分析年龄、性别的作用。结果发现, 校正年龄后, 头部指标中头围的遗传度(男66%, 女66%)较高; 面部指标中, 容貌面高的遗传度(男73%, 女84%)最高, 其次为鼻宽(男57%, 女67%)、眼内角间宽(男57%, 女50%)和额最小宽(男50%, 女50%); 头长(男64%, 女25%)、头宽(男26%, 女82%)、眼外角间宽(男76%, 女34%)和容貌耳长(男23%, 女70%)的遗传度存在一定的性别差异。表明遗传因素与环境因素对学龄双生子儿童的头面部发育均有一定影响, 其中遗传因素对男女头围及容貌面高、男性头长和眼外角间宽、女性头宽、鼻宽、口宽、容貌耳长的影响相对较大。     

Assumptions and Properties of Limiting Pathway Models for Analysis of Epistasis in Complex Traits

For most complex traits, results from genome-wide association studies show that the proportion of the phenotypic variance attributable to the additive effects of individual SNPs, that is, the heritability explained by the SNPs, is substantially less than the estimate of heritability obtained by standard methods using correlations between relatives. This difference has been called the “missing heritability”. One explanation is that heritability estimates from family (including twin) studies are biased upwards. Zuk et al. revisited overestimation of narrow sense heritability from twin studies as a result of confounding with non-additive genetic variance. They propose a limiting pathway (LP) model that generates significant epistatic variation and its simple parametrization provides a convenient way to explore implications of epistasis. They conclude that over-estimation of narrow sense heritability from family data (‘phantom heritability’) may explain an important proportion of missing heritability. We show that for highly heritable quantitative traits large phantom heritability estimates from twin studies are possible only if a large contribution of common environment is assumed. The LP model is underpinned by strong assumptions that are unlikely to hold, including that all contributing pathways have the same mean and variance and are uncorrelated. Here, we relax the assumptions that underlie the LP model to be more biologically plausible. Together with theoretical, empirical, and pragmatic arguments we conclude that in outbred populations the contribution of additive genetic variance is likely to be much more important than the contribution of non-additive variance.     

Genomic Heritability: What Is It?

Whole-genome regression methods are being increasingly used for the analysis and prediction of complex traits and diseases. In human genetics, these methods are commonly used for inferences about genetic parameters, such as the amount of genetic variance among individuals or the proportion of phenotypic variance that can be explained by regression on molecular markers. This is so even though some of the assumptions commonly adopted for data analysis are at odds with important quantitative genetic concepts. In this article we develop theory that leads to a precise definition of parameters arising in high dimensional genomic regressions; we focus on the so-called genomic heritability: the proportion of variance of a trait that can be explained (in the population) by a linear regression on a set of markers. We propose a definition of this parameter that is framed within the classical quantitative genetics theory and show that the genomic heritability and the trait heritability parameters are equal only when all causal variants are typed. Further, we discuss how the genomic variance and genomic heritability, defined as quantitative genetic parameters, relate to parameters of statistical models commonly used for inferences, and indicate potential inferential problems that are assessed further using simulations. When a large proportion of the markers used in the analysis are in LE with QTL the likelihood function can be misspecified. This can induce a sizable finite-sample bias and, possibly, lack of consistency of likelihood (or Bayesian) estimates. This situation can be encountered if the individuals in the sample are distantly related and linkage disequilibrium spans over short regions. This bias does not negate the use of whole-genome regression models as predictive machines; however, our results indicate that caution is needed when using marker-based regressions for inferences about population parameters such as the genomic heritability.     

Quantitative trait loci for bone lengths on chromosome 5 using dual energy X-Ray absorptiometry imaging in the Twins UK cohort

Human height is a highly heritable and complex trait but finding important genes has proven more difficult than expected. One reason might be the composite measure of height which may add heterogeneity and noise. The aim of this study was to conduct a genome-wide linkage scan to identify quantitative trait loci (QTL) for lengths of spine, femur, tibia, humerus and radius. These were investigated as alternative measures for height in a large, population-based twin sample with the potential to find genes underlying bone size and bone diseases. 3,782 normal Caucasian females, 18-80 years old, with whole body dual energy X-ray absorptiometry (DXA) images were used. A novel and reproducible method, linear pixel count (LPC) was used to measure skeletal sizes on DXA images. Intraclass correlations and heritability estimates were calculated for lengths of spine, femur, tibia, humerus and radius on monozygotic (MZ; n = 1,157) and dizygotic (DZ; n = 2,594) twins. A genome-wide linkage scan was performed on 2000 DZ twin subjects. All skeletal sites excluding spine were highly correlated. Intraclass correlations showed results for MZ twins to be significantly higher than DZ twins for all traits. Heritability results were as follows: spine, 66%; femur, 73%; tibia, 65%; humerus, 57%; radius, 68%. Results showed reliable evidence of highly suggestive linkage on chromosome 5 for spine (LOD score = 3.0) and suggestive linkage for femur (LOD score = 2.19) in the regions of 105cM and 155cM respectively. We have shown strong heritability of all skeletal sizes measured in this study and provide preliminary evidence that spine length is linked to the chromosomal region 5q15-5q23.1. Bone size phenotype appears to be more useful than traditional height measures to uncover novel genes. Replication and further fine mapping of this region is ongoing to determine potential genes influencing bone size and diseases affecting bone.     

Quantitative genetic tools for insecticide resistance risk assessment: estimating the heritability of resistance

Quantitative genetic studies of resistance can provide estimates of genetic parameters not available with other types of genetic analyses. Three methods are discussed for estimating the amount of additive genetic variation in resistance to individual insecticides and subsequent estimation of the heritability (h2) of resistance. Sibling analysis and offspring-parent regression permit direct estimates of h2 by comparing the resistance phenotypes of individuals of known relatedness. Threshold trait analyses, performed on data from selection experiments, provide estimates of realized heritability. Procedures are outlined for predicting changes in resistance to insecticides based on h2 estimates. Quantitative genetic theory is examined as it relates to resistance and resistance as a quantitative trait; quantitative genetic methods also are unique in providing estimates of genetic correlations between traits. Comments are included on estimates of genetic correlation between resistance and phenotypic traits (e.g., development time) and how they may be used to predict changes in the genetic aspects of phenology that result from insecticide applications (i.e., to predict how the reproductive capacity of future generations will differ from that of the treated generation).     

Genetic and environmental influences on skeletal muscle phenotypes as a function of age and sex in large, multigenerational families of African heritage.

The aim of this study was to estimate the heritability of and environmental contributions to skeletal muscle phenotypes (appendicular lean mass and calf muscle cross-sectional area) in subjects of African descent and to determine whether heritability estimates are impacted by sex or age. Body composition was measured by dual-energy X-ray absorptiometry and computed tomography in 444 men and women aged 18 yr and older (mean: 43 yr) from eight large, multigenerational Afro-Caribbean families (family size range: 21-112). Using quantitative genetic methods, we estimated heritability and the association of anthropometric, lifestyle, and medical variables with skeletal muscle phenotypes. In the overall group, we estimated the heritability of lean mass and calf muscle cross-sectional area (h(2) = 0.18-0.23, P < 0.01) and contribution of environmental factors to these phenotypes (r(2) = 0.27-0.55, P < 0.05). In our age-specific analysis, the heritability of leg lean mass was lower in older vs. younger individuals (h(2) = 0.05 vs. 0.23, respectively, P = 0.1). Sex was a significant covariate in our models (P < 0.001), although sex-specific differences in heritability varied depending on the lean mass phenotype analyzed. High genetic correlations (rho(G) = 0.69-0.81; P < 0.01) between different lean mass measures suggest these traits share a large proportion of genetic components. Our results demonstrate the heritability of skeletal muscle traits in individuals of African heritage and that heritability may differ as a function of sex and age. As the loss of skeletal muscle mass is related to metabolic abnormalities, disability, and mortality in older individuals, further research is warranted to identify specific genetic loci that contribute to these traits in general and in a sex- and age-specific manner.     

Dominance and environmental variances: their effect on heritabilities estimated from twin data

A method for partitioning genetic variance estimated from twin data into additive and dominance variances was presented using Falconer's variance component model. The effects of dominance and environmental variances on a number of heritability estimates were also reviewed. A heritability estimate, based on the analysis of variance and the genetic variance estimates presented by HASEMAN and ELSTON and CHRISTIAN et al. which utilizes all available information from twin data, was proposed and discussed. This estimate seems to be the least affected by fluctuations in the magnitudes of dominance and environmental variances.     

Primate population studies at Polonnaruwa. II. Heritability of body measurements in a natural population of toque macaques (Macaca sinica)

The heritability of quantitative traits, or the proportion of phenotypic variation due to additive genetic or heritable effects, plays an important role in determining the evolutionary response to natural selection. Most quantitative genetic studies are performed in the laboratory, due to difficulty in obtaining genealogical data in natural populations. Genealogies are known, however, from a unique 20-year study of toque macaques (Macaca sinica) at Polonnaruwa, Sri Lanka. Heritability in this natural population was, therefore, estimated. Twenty-seven body measurements representing the lengths and widths of the head, trunk, extremities, and tail were collected from 270 individuals. The sample included 172 offspring-mother pairs from 39 different matrilineal families. Heritabilities were estimated using traditional mother-offspring regression and maximum likelihood methods which utilize all genealogical relationships in the sample. On the common assumption that environmental (including social) factors affecting morphology were randomly distributed across families, all but two of the traits (25 of 27) were significantly heritable, with an average heritability of 0.51 for the mother-offspring analysis and 0.56 for the maximum likelihood analysis. Heritability estimates obtained from the two analyses were very similar. We conclude that the Polonnaruwa macaques exhibit a comparatively moderate to high level of heritability for body form. © 1992 Wiley-Liss, Inc.     

Birth wantedness reports: A look forward and a look back

Abstract

The majority of research indicates that estimates of heritability are not generalizable beyond the specific sample on which they have been calculated. This research has been limited, however, in its scope. The present set of investigations center upon an examination of previously reported heritability estimates for the scales of the Minnesota Multiphasic Personality Inventory (MMPI). The first investigation correlates the estimates for eight samples derived from a variety of published studies. The second investigation correlates the DZ twin pair and MZ twin pair intraclass correlations from four of the first investigation's samples. The third investigation correlates the estimates from one study in which the same sample was tested twice over a period of less than five years. It is concluded that no evidence is available for the generalizability of these estimates of MMPI scale heritability either across samples or even across time with the same sample.     

Genetic Control of Glycolysis in Human Erythrocytes

We have studied heritability of the concentration of each glycolytic intermediate and adenine nucleotide in the cytosol of human erythrocytes obtained from a random sample of apparently healthy young individuals. Preliminary to analysis of heritability, each trait was statistically described and the effects attributable to variation in measured concomitants were removed by regression. Heritability was estimated using the family-set method. This method removes covariances between the index case, sibling and first cousin, due to those environmental determinants of the phenotypic values that are shared with a matched, unrelated control member of the family set. It also removes covariances due to environments that are shared by siblings and first cousins. Heritability was estimated by employing the fact that the variance of differences between first cousins minus the variance of differences between full siblings estimates three-fourths of the additive genetic variance. The heritability estimates for G6P†, F6P, ATP and some other metabolite concentrations are high and significantly greater than zero. The heritabilities of G6P and F6P are likely attributable to genetic variation in the in vivo activity of HK and/or PFK, because the concentrations of these metabolites are tightly controlled by the two regulatory enzymes. Statistically significant heritability estimates for HK and PFK mass action ratios strongly suggest genes are responsible for a portion of the quantitative variation in these enzyme activities. Since HK and PFK regulate glycolysis and the production of ATP, genetic variation in their activities might be causally related to the heritability of ATP concentration.     

Comparing sensory experience in bitter taste perception of phenylthiocarbamide within and between human twins and singletons: intrapair differences in thresholds and genetic variance estimates

BACKGROUND: Quantitative genetic studies revealed that not all of the phenotypic variance in PTC taste perception is heritable. AIM: To study quantitative variations in PTC tasting ability in twins and to estimate heritability of PTC taste perception on the taste of twin data on males and females sexes separately. SUBJECTS AND METHODS: The data for PTC taste sensitivity following the classic method of Harris & Kalmus (1949) were collected on a sample of 141 twin pairs (66 MZ and 75 DZ) and 275 singletons (128 males and 147 females) from Chandigarh, India. Genetic analyses were performed following Christian (1979), Donner (1986) and Sham (1998). RESULTS: Frequency of non-tasters was similar in twins (33 %) and singletons (32 %), but significant sex differences were observed. No differences were found between zygosities for mean thresholds. Similarly, no evidence of variance heterogeneity and environmental covariance was seen between zygosities. Since no basic assumption of the twin method was found violated, within-pair estimates of genetic variance would be unbiased. These estimates were highly significant in both males and females. However, dominance and additive components of genetic variance were found to differ between sexes. CONCLUSION: PTC thresholds do not seem to be significantly affected by environmental factors as no variance inequality was observed between twin zygosities. Intensity of bitterness (scalar dimensions) of PTC is a separate trait having no commonality with the genetic basis of recognition threshold for PTC tasting ability. The receptors recognizing bitter taste are different from the receptors determining intensity of taste. The absolute difference between co-twins in PTC thresholds can be used as a simple tool in the twin zygosity diagnosis. The results show that none of the MZ co-twins had manifested difference of more than 3 in their PTC threshold.