Biological and environmental sources of variation in plasma lipids and lipoproteins: the Jerusalem Lipid Research Clinic

We have previously described a general pattern of homogeneity in genetic and cultural determinants of blood lipids and lipoproteins among the major origin groups in the Israeli population. This paper reports on these determinants of total plasma cholesterol (TC), triglyceride (TG), low- and high-density lipoprotein cholesterol (LDL-C, HDL-C), and of the HDL-C/TC ratio, estimated from the total sample of 4,000 families whose members were examined in the Jerusalem Lipid Research Clinic. Both genetic (h2) and cultural (c2) components of inheritance were significant for all lipid variables. Under the most parsimonious model genetic heritability (h2) ranges from 0.45 for LDL-C, 0.47 for HDL-C to 0.64 for HDL-C/TC ratio. Cultural heritability (c2) was 0.03 for LDL-C, 0.04 for TC, 0.05 for TG and 0.07 for HDL-C and HDL-C/TC ratio. Within this population, as in others, genetic factors appear to be the major determinants of lipid variation, suggesting relative homogeneity of environmental correlates of plasma lipids.     

Heterogeneity in the biological and cultural determinants of high-density lipoprotein cholesterol in five North American populations: the Lipid Research Clinics Family Study

Heterogeneity in the source of familial resemblance for high-density lipoprotein (HDL) cholesterol in 5 different Lipid Research Clinics (Cincinnati, Iowa, Minnesota, Oklahoma and Stanford) was assessed using a general linear model for cultural and biological inheritance. No evidence of heterogeneity was found in any of the parameters of the model. Under the most parsimonious hypothesis, using data pooled over all clinics, genetic and cultural heritability were both significant and were estimated to be 0.52 +/- 0.04 and 0.09 +/- 0.02, respectively; there was cultural transmission but no maternal effects; marital and nontransmitted sibship environmental resemblance were significant.     

Genetic regulation of plasma and red blood cell magnesium concentrations in man. I. Univariate and bivariate path analyses.

This paper concerns an analysis of family resemblance for magnesium concentrations, based on data from nuclear families and twins. Neither red blood cell magnesium nor plasma magnesium varies with age in children (under 20 years of age). Whereas adult plasma magnesium varies linearly with age, the red cell magnesium clearly showed a nonlinear trend: quadratic for males and a fifth-degree polynomial for females. Transformed magnesium concentrations generated six correlations in nuclear families and twins for each of the two traits. Separate univariate analyses, using a simple linear model with four parameters, strongly suggested that genetic factors are primarily responsible for the observed family resemblance. Both traits were then analyzed simultaneously using a simple bivariate model. We found that one common genetic factor alone could not explain all the 24 correlations generated for the bivariate analysis. The most parsimonious model involved only three parameters: genetic heritability for red blood cell magnesium (.922 +/- .014), genetic heritability for plasma magnesium (.721 +/- .040), and the genetic correlation between the two traits (.233 +/- .040).     

Heterogeneity between populations for multifactorial inheritance of plasma lipids

A general linear model was described for multifactorial inheritance of the two plasma lipids, total cholesterol (CH), and triglyceride (TG). Analyses of two separate studies, the Honolulu Heart Study (HHS) and the Cincinnati Lipid Research Clinic (LRC), indicated some heterogeneity. Whereas the sibling environmental effect (b) was the only source of heterogeneity between the two studies for TG, the correlation between marital environments (u) may also be considered as a source of heterogeneity for CH. Under parsimonious hypothesis, intergenerational differences in heritabilities were not found to be significant for either trait (y1 = y2 = z1 = z2 = 1). Maternal effects were significant for CH but not for TG. Correlations between marital environments (u1 and u2) were not significant for TG, and may be considered nonsignificant for CH also under parsimonious hypotheses. In any case, the genetic (h2) and cultural (c2) heritabilities cannot be considered to be heterogeneous between the two studies. Based on pooled data, parsimonious hypothesis yields: h2 = .594 +/- .041 and c2 = .035 +/- .008 for CH, and h2 = .259 +/- .034 and c2 = .108 +/- .014 for TG.     

Beyond DNA: integrating inclusive inheritance into an extended theory of evolution

Many biologists are calling for an 'extended evolutionary synthesis' that would 'modernize the modern synthesis' of evolution. Biological information is typically considered as being transmitted across generations by the DNA sequence alone, but accumulating evidence indicates that both genetic and non-genetic inheritance, and the interactions between them, have important effects on evolutionary outcomes. We review the evidence for such effects of epigenetic, ecological and cultural inheritance and parental effects, and outline methods that quantify the relative contributions of genetic and non-genetic heritability to the transmission of phenotypic variation across generations. These issues have implications for diverse areas, from the question of missing heritability in human complex-trait genetics to the basis of major evolutionary transitions.     

Resolution of genetic and cultural inheritance in twin families by path analysis: application to HDL-cholesterol.

A path model and associated statistical method for the analysis of data on twin families are introduced and applied to high density lipoprotein cholesterol (HDL-c) observations in the Swedish Twin Family Study. The proposed path model incorporates both genetic and environmental sources of familial resemblance, maternal environmental effects, intergenerational differences in heritabilities, marital resemblance due to either primary or secondary phenotypic homogamy, and twin residual environmental correlations. Application of the model to HDL-c levels resulted in parameter estimates consistent with those reported in earlier reviews and in the analysis of nuclear family and twin data. Genetic heritability was estimated as h2 = .363 +/- .243, cultural heritability as c2 = .187 +/- .082, and the proportion of phenotypic variance due to residual environmental effects as r2 = .450 +/- .207. Although the parameter estimates were comparable, the statistical tests of hypotheses were, relative to other designs, of low statistical power. It appears that environmental indices are necessary for powerful tests of hypotheses.     

Determinants of blood pressure in Japanese-American families

Summary Blood pressure gave evidence for genetic heritability (0.24 for systolic, 0.19 for diastolic) and for cultural heritability (0.16 for systolic, 0.09 for diastolic in children) in a sample of Japanese-American families. A small but significant fraction of cultural inheritance was due to maternal effects, possibly mediated through dietary habits. There was no convincing evidence for major loci causing hypertension in this population, and the polymorphism proposed by Platt was excluded as a principal cause of hypertension.     

Inclusive heritability: combining genetic and non‐genetic information to study animal behavior and culture

Phenotypic variance results from variation in biological information possessed by individuals. Quantitative geneticists often strive to partition out all environmental variance to measure heritability. Behavioral biologists and ecologists however, require methods to integrate genetic and environmental components of inherited phenotypic variance in order to estimate the evolutionary potential of traits, which encompasses any form of information that is inherited. To help develop this integration, we build on the tools of quantitative genetics and offer the concept of ‘inclusive heritability’ which identifies and unifies the various mechanisms of information transmission across generations. A controversial component of non‐genetic information is animal culture, which is the part of phenotypic variance inherited through social learning. Culture has the unique property of being transmitted horizontally and obliquely, as well as vertically. Accounting for cultural variation would allow us to examine a broader range of evolutionary mechanisms. Culture may, for instance, produce behavioral isolating mechanisms leading to speciation. To advance the study of animal culture, we offer a definition of culture that is rooted in quantitative genetics. We also offer four testable criteria to determine whether a trait is culturally inherited. These criteria may constitute a conceptual tool to study animal culture. We briefly discuss methods to partition out cultural variance. Several authors have recently called for ‘modernizing the modern synthesis’ by including non‐genetic factors such as epigenetics and phenotypic plasticity in order to more fully explain phenotypic evolution. Here, we further propose to broaden the concept of inheritance by incorporating the cultural component of behavior. Applying the concept of inclusive heritability may advance the integration of multiple forms of inheritance into the study of evolution.     

Family resemblance for glucose tolerance in a Melanesian population, the Tolai

Path analysis of family resemblance for plasma glucose concentration, 2 h after an oral glucose challenge, failed to detect significant genetic heritability. There were no intergenerational differences and marital resemblance was moderate. Over one-third of sibling environmental similarity was due to non-inherited factors. Cultural inheritance was very strong, tending to mimic genetic inheritance, and cultural heritability was considerable. Measures of obesity were included in the environmental index, an estimate of familial environment, in this analysis, for comparability with previous studies. Since obesity appears, in part, to be a heritable trait, in future studies a bivariate approach to family resemblance for both glucose tolerance and obesity could yield important additional insight.     

Sex-Specific Heritability of Spontaneous Lipid Levels in an Extended Pedigree of Indian-Origin Rhesus Macaques (Macaca mulatta)

The rhesus macaque is an important model for human atherosclerosis but genetic determinants of relevant phenotypes have not yet been investigated in this species. Because lipid levels are well-established and heritable risk factors for human atherosclerosis, our goal was to assess the heritability of lipoprotein cholesterol and triglyceride levels in a single, extended pedigree of 1,289 Indian-origin rhesus macaques. Additionally, because increasing evidence supports sex differences in the genetic architecture of lipid levels and lipid metabolism in humans and macaques, we also explored sex-specific heritability for all lipid measures investigated in this study. Using standard methods, we measured lipoprotein cholesterol and triglyceride levels from fasted plasma in a sample of 193 pedigreed rhesus macaques selected for membership in large, paternal half-sib cohorts, and maintained on a low-fat, low cholesterol chow diet. Employing a variance components approach, we found moderate heritability for total cholesterol (h²=0.257, P=0.032), LDL cholesterol (h²=0.252, P=0.030), and triglyceride levels (h²=0.197, P=0.034) in the full sample. However, stratification by sex (N=68 males, N=125 females) revealed substantial sex-specific heritability for total cholesterol (0.644, P=0.004, females only), HDL cholesterol (0.843, P=0.0008, females only), VLDL cholesterol (0.482, P=0.018, males only), and triglyceride levels (0.705, P=0.001, males only) that was obscured or absent when sexes were combined in the full sample. We conclude that genes contribute to spontaneous variation in circulating lipid levels in the Indian-origin rhesus macaque in a sex-specific manner, and that the rhesus macaque is likely to be a valuable model for sex-specific genetic effects on lipid risk factors for human atherosclerosis. These findings are a first-ever report of heritability for cholesterol levels in this species, and support the need for expanded analysis of these traits in this population.     

Power of the joint segregation analysis method for testing mixed major-gene and polygene inheritance models of quantitative traits

Understanding the genetic architecture of quantitative traits can greatly assist the design of strategies for their manipulation in plant-breeding programs. For a number of traits, genetic variation can be the result of segregation of a few major genes and many polygenes (minor genes). The joint segregation analysis (JSA) is a maximum-likelihood approach for fitting segregation models through the simultaneous use of phenotypic information from multiple generations. Our objective in this paper was to use computer simulation to quantify the power of the JSA method for testing the mixed-inheritance model for quantitative traits when it was applied to the six basic generations: both parents (P₁ and P₂), F₁, F₂, and both backcross generations (B₁ and B₂) derived from crossing the F₁ to each parent. A total of 1968 genetic model-experiment scenarios were considered in the simulation study to quantify the power of the method. Factors that interacted to influence the power of the JSA method to correctly detect genetic models were: (1) whether there were one or two major genes in combination with polygenes, (2) the heritability of the major genes and polygenes, (3) the level of dispersion of the major genes and polygenes between the two parents, and (4) the number of individuals examined in each generation (population size). The greatest levels of power were observed for the genetic models defined with simple inheritance; e.g., the power was greater than 90% for the one major gene model, regardless of the population size and major-gene heritability. Lower levels of power were observed for the genetic models with complex inheritance (major genes and polygenes), low heritability, small population sizes and a large dispersion of favourable genes among the two parents; e.g., the power was less than 5% for the two major-gene model with a heritability value of 0.3 and population sizes of 100 individuals. The JSA methodology was then applied to a previously studied sorghum data-set to investigate the genetic control of the putative drought resistance-trait osmotic adjustment in three crosses. The previous study concluded that there were two major genes segregating for osmotic adjustment in the three crosses. Application of the JSA method resulted in a change in the proposed genetic model. The presence of the two major genes was confirmed with the addition of an unspecified number of polygenes. Received: 18 August 2000 / Accepted: 9 March 2001     

Familial aggregation of lipids and lipoproteins in families ascertained through random and nonrandom probands in the Iowa Lipid Research Clinics family study

The aggregation of lipids [total cholesterol (CH) and triglyceride (TG)] and lipoproteins [high-density lipoprotein cholesterol (HDL) and low-density lipoprotein cholesterol (LDL)] in families ascertained through random and nonrandom probands in the Iowa Lipid Research Clinics family study was examined. Nonrandom probands were selected because their lipid levels (at a prior screening visit) exceeded a certain pre-specified threshold. The statistical method conditions the likelihood function on the actual event that the proband's value is beyond the threshold. This method allows for estimation of the path model parameters in randomly and nonrandomly ascertained families jointly and separately, thus enabling tests of heterogeneity between the two types of samples. Marked heterogeneity between the random and the hyperlipidemic samples is detected in the multifactorial transmission for TG and HDL, and moderate heterogeneity is detected for CH and LDL, with a pattern of higher genetic heritability estimates in the random than nonrandom samples. The observed pattern of heterogeneity is compatible with a higher prevalence in the random sample of certain dyslipoproteinemias that are associated with nonelevated lipids. For the random samples, genetic heritabilities are higher for CH and HDL (about 60%) than for TG and LDL (about 50%). For the nonrandom samples those estimates are about 45, 40, 35 and 30% for HDL, CH, LDL and TG, respectively. Little to no cultural (familial environmental) heritability is evident for CH and LDL, although 10-20% of the phenotypic variance is due to cultural factors for TG and HDL. These results suggest that the etiologies for lipids and lipoproteins may be quite different in random versus hyperlipidemic samples.     

An experimental comparison of selection alternatives to plateaued response

Three alternative selection methods for extending selection limits or breaking response plateaus were compared over ten generations in a replicated model experiment using two unrelated populations of Drosophila melanogaster that no longer responded to purebred selection for high egg number, a heterotic polygenic trait. The three methods were: (1) reciprocal recurrent selection (RRS) with selection within each of the plateaued populations based solely on crossbred performance, (2) a modification of reciprocal recurrent selection (MRRS) with selection within each population based on both purebred and crossbred performance, and (3) purebred selection within a new synthetic population formed by crossing the two plateaued populations.--Conflicting estimates were obtained for heritability of purebred egg number in each of the plateaued populations. The realized heritability values and estimates from diallel analyses indicated an absence of additive genetic variation for both populations; however, estimates from conventional intraclass correlation methods were positive. The diallel analyses revealed significant amounts of nonadditive gene effects for purebred egg number in each population, while the significant gene effects for crossbred egg numbers were additive. Estimates of the genetic correlation between purebred and crossbred egg number were negative (-0.85 +/- 0.68 and -0.32 +/- 0.25) for the two base populations.--All three alternatives to continued purebred selection gave significant responses, with the average gain per generation from MRRS being significantly superior to the other two methods. Observed purebred and crossbred responses under RRS were in agreement with quantitative genetic theory. Such was not the case for MRRS, which suggested the possibility of major gene segregation.--Evidence supporting a negative genetic correlation between purebred and crossbred performance and the possibility of overdominance is presented and discussed.     

家族高发性2型糖尿病的遗传模式研究

对1999～2000年门诊及住院的家族高发性2型糖尿病患者为先证者的136个大家系进行研究,以探讨该病的遗传模式。对家系人群采用Falconer 法估算遗传率,用Penrose法进行多基因分析,并用S.A.G.E-REGD软件拟合A型回归Logistic模型进行复合分离分析的方法,对家族高发性2型糖尿病家系进行研究。结果表明,136个大家系的2型糖尿病遗传率为94.07%±5.84%,提示在这些家系中可能有显性主基因存在。多基因分析研究表明,在该人群中,2型糖尿病因性别不同而存在两种遗传模式。复合分离分析拒绝单纯环境模型、非传递模型、共显性模型,接受隐性模型和显性模型,但隐性模型为最佳遗传模式。因此,2型糖尿病具有高度的遗传性和遗传异质性,总体表现为多因子遗传,在部分遗传背景较一致的家系人群中可能存在由主要基因决定的常染色体显性遗传。 Abstract:This study is to explore the genetic model of type 2 diabetes mellitus (type 2 DM) among the hereditary family.One hundred and thirty-six pedigrees of familial type 2 DM were studied.The heritability of type 2 DM was estimated according to Falconer's method and the multi-factorial inheritance analyzed according to Penrose's method.Complex segregation analysis was performed using S.A.G.E-REGD.The heritability of familial type 2 DM was 9407%±5.84%.Dominant major gene might influence the genesis of type 2 DM.Analysis of multi-factorial inheritance indicated that there be two genetic patterns respectively in male and female populations.By complex segregation analysis,environment,non-transmitted and co-dominant inheritance were rejected.Autosomal dominant (AD) inheritance and autosomal recessive (AR) inheritance was accepted but AR inheritance was the best pattern.This study suggested that type 2 DM had significant heritability and genetic heterogeneity,which appeared to be a disease of multi-factorial inheritance generally and autosomal dominant (AD) inheritance in part of pedigrees.     

植物数量性状遗传体系的分离分析方法研究

在传统的数量性状多基因遗传模型基础上提出主基因-多基因遗传模型具普遍性,纯主基因或纯多基因遗传模型只是其特例。由此初步建立了植物数量性状遗传体系分离分析方法。目前该方法可以检验2～3个主基因的个别遗传效应、多基因整体的遗传效应和两者的遗传率。本文介绍这种分离分析方法的研究经过、主要进展及应用效果,并以实例说明其分析步骤、方法和效果。     

Heritability of age at menarche in girls from the Fels Longitudinal Study

Menarche is the hallmark maturational event of female childhood. Many studies indicated a significant genetic contribution to the timing of the onset of menstruation, but most of these studies were limited by the use of retrospective data and by the use of data from only certain types of relatives (i.e., mothers and daughters, sisters, or twin sisters). The primary goal of this study was to use a modern maximum likelihood quantitative genetic method to estimate the heritability (h(2)) of age at menarche, using familial data collected over the course of the 74-year-old Fels Longitudinal Study. The secondary goal was to review earlier studies of the heritability of age at menarche. The study of the heritability of age at menarche presented here is unique for two reasons. First, because of the Fels Longitudinal Study's serial design, age-at-menarche data were collected prospectively from most participants. Second, because the Fels Longitudinal Study is a family study that has been conducted for decades, age-at-menarche data are available from many types of female relatives spanning multiple households and generations. The best-fitting and most parsimonious quantitative genetic model included provision for a secular decrease in age at menarche, and estimated the h(2) of age at menarche to be 0.49+/- 0.13 (95% confidence interval of h(2),=0.24-0.73). The results of this study are in general agreement with the findings of most previous studies of genetic influences on age at menarche, and suggest that it is reasonable to consider it well-established that approximately half the phenotypic variation among girls from developed nations in the timing of menarche is due to genetic factors.     

ON THE LOW HERITABILITY OF LIFE-HISTORY TRAITS

Life-history traits such as longevity and fecundity often show low heritability. This is usually interpreted in terms of Fisher's fundamental theorem to mean that populations are near evolutionary equilibrium and genetic variance in total fitness is low. We develop the causal relationship between metric traits and life-history traits to show that a life-history trait is expected to have a low heritability whether or not the population is at equilibrium. This is because it is subject to all the environmental variation in the metric traits that affect it plus additional environmental variation. There is no simple prediction regarding levels of additive genetic variance in life-history traits, which may be high at equilibrium. Several other patterns in the inheritance of life-history traits are readily predicted from the causal model. These include the strength of genetic correlations between life-history traits, levels of nonadditive genetic variance, and the inevitability of genotype-environment interaction.     

Path analysis of palmar ridge counts.

The methods for path analysis of family resemblance (Rao et al., '74) are employed to test hypotheses concerning the inheritance of a-b, b-c and c-d palmar ridge counts using the correlation data of Pateria ('74). Homogeneity chi-square tests of the various familial correlations provide no evidence for sex-linkage of either kind, and also suggest that maternal effects are absent. The path coefficient model employed here involves heritability (additive) and common sibling environment. Variance components show that both heritability and common environment are significant, and account for most of the variation at each of the three ridge count area; b-c has the highest heritability, significantly higher than that for a-b or c-d.     

Environment-sensitive epigenetics and the heritability of complex diseases

Genome-wide association studies have thus far failed to explain the observed heritability of complex human diseases. This is referred to as the "missing heritability" problem. However, these analyses have usually neglected to consider a role for epigenetic variation, which has been associated with many human diseases. We extend models of epigenetic inheritance to investigate whether environment-sensitive epigenetic modifications of DNA might explain observed patterns of familial aggregation. We find that variation in epigenetic state and environmental state can result in highly heritable phenotypes through a combination of epigenetic and environmental inheritance. These two inheritance processes together can produce familial covariances significantly higher than those predicted by models of purely epigenetic inheritance and similar to those expected from genetic effects. The results suggest that epigenetic variation, inherited both directly and through shared environmental effects, may make a key contribution to the missing heritability.     

Genetic analysis of the structure of predisposition to diabetes mellitus. III. Genetic heterogeneity of diabetes mellitus with different ages of onset

The results of genetical-epidemiological analysis of the three conventional forms of diabetes mellitus (DM) differentiated for age-at-onset are presented (the form I - from 0 to 29 y. the form II - from 30 to 59 y. the form III - 60 y. and older). The estimates of heritability of liability to the forms I, II and III of DM were 0.57, 0.70 and 0.65, respectively. It was shown that genetic components of the forms I and II are virtually different: genetic correlation between these forms was rA = 0.216 +/- 0.203, which is statistically insignificant. These data support the hypothesis assuming genetic independence of juvenile and adult forms of DM. On the other hand, the forms II and III were found to have an essential number of genes in common: genetic correlation was rA = 0.495 +/- 0.134, being significant at the 5% level. Thus, the forms II and III of DM are not to be considered as two genetically distinct diseases. The low recurrence risks of the form I for siblings (not more than 3.6%) allow to reject the hypothesis of simple monogenic inheritance of juvenile DM and to propose multifactorial nature of the disease.