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Biomarkers may be useful endophenotypes for genetic studies if they share genetic sources of variation with the outcome, for example, with all-cause mortality. Australian adult study participants who had reported their parental survival information were included in the study: 14,169 participants had polygenic risk scores (PRS) from genotyping and up to 13,365 had biomarker results. We assessed associations between participants’ biomarker results and parental survival, and between biomarker results and eight parental survival PRS at varying p-value cut-offs. Survival in parents was associated with participants’ serum bilirubin, C-reactive protein, HDL cholesterol, triglycerides and uric acid, and with LDL cholesterol for participants’ fathers but not for their mothers. PRS for all-cause mortality were associated with liver function tests (alkaline phosphatase, butyrylcholinesterase, gamma-glutamyl transferase), metabolic tests (LDL and HDL cholesterol, triglycerides, uric acid), and acute-phase reactants (C-reactive protein, globulins). Association between offspring biomarker results and parental survival demonstrates the existence of familial effects common to both, while associations between biomarker results and PRS for mortality favor at least a partial genetic cause of this covariation. Identification of genetic loci affecting mortality-associated biomarkers offers a route to the identification of additional loci affecting mortality.
Mortality risk is known to be associated with many physiological or biochemical risk factors, and polygenic risk scores (PRSs) may offer an additional or alternative approach to risk stratification. We have compared the predictive value of common biochemical tests, PRSs and information on parental survival in a cohort of twins and their families. Common biochemical test results were available for up to 13,365 apparently healthy men and women, aged 17−93 years (mean 49.0, standard deviation [SD] 13.7) at blood collection. PRSs for longevity were available for 14,169 study participants and reported parental survival for 25,784 participants. A search for information on date and cause of death was conducted through the Australian National Death Index, with median follow-up of 11.3 years. Cox regression was used to evaluate associations with mortality from all causes, cancers, cardiovascular diseases and other causes. Linear relationships with all-cause mortality were strongest for C-reactive protein, gamma-glutamyl transferase, glucose and alkaline phosphatase, with hazard ratios (HRs) of 1.16 (95% CI [1.07, 1.24]), 1.15 (95% CI 1.04–1.21), 1.13 (95% CI [1.08, 1.19]) and 1.11 (95% CI [1.05, 1.88]) per SD difference, respectively. Significant nonlinear effects were found for urea, uric acid and butyrylcholinesterase. Lipid risk factors were not statistically significant for mortality in our cohort. Family history and PRS showed weaker but significant associations with survival, with HR in the range 1.05 to 1.09 per SD difference. In conclusion, biochemical tests currently predict long-term mortality more strongly than genetic scores based on genotyping or on reported parental survival.
Biomarkers diagnose, predict or assess the risk of disease, and studies of the effects of genetic variation on biomarker phenotypes in the general population complement studies on patients diagnosed with disease. This paper traces the evolution of studies on biomarker genetics over the past 40 years through examples drawn from the work of Professor Martin and his colleagues.
Persistent tobacco use and excessive alcohol consumption are major public health concerns worldwide. Both alcohol and nicotine dependence (AD, ND) are genetically influenced complex disorders that exhibit a high degree of comorbidity. To identify gene variants contributing to one or both of these addictions, we first conducted a pooling-based genomewide association study (GWAS) in an Australian population, using Illumina Infinium 1M arrays. Allele frequency differences were compared between pooled DNA from case and control groups for: (1) AD, 1224 cases and 1162 controls; (2) ND, 1273 cases and 1113 controls; and (3) comorbid AD and ND, 599 cases and 488 controls. Secondly, we carried out a GWAS in independent samples from the Netherlands for AD and for ND. Thirdly, we performed a meta-analysis of the 10, 000 most significant AD- and ND-related SNPs from the Australian and Dutch samples. In the Australian GWAS, one SNP achieved genomewide significance (p < 5 x 10-8) for ND (rs964170 in ARHGAPlOon chromosome 4, p = 4.43 x 10”8) and three others for comorbid AD/ND (rs7530302 near MARK1 on chromosome 1 (p = 1.90 x 10-9), rs1784300 near DDX6 on chromosome 11 (p = 2.60 x 10-9) and rs12882384 in KIAA1409 on chromosome 14 (p = 4.86 x 10-8)). None of the SNPs achieved genomewide significance in the Australian/Dutch meta-analysis, but a gene network diagram based on the top-results revealed overrepre-sentation of genes coding for ion-channels and cell adhesion molecules. Further studies will be requirec before the detailed causes of comorbidity between AC and ND are understood.
Genome-wide association analysis on monozygotic twin-pairs offers a route to discovery of gene–environment interactions through testing for variability loci associated with sensitivity to individual environment/lifestyle. We present a genome-wide scan of loci associated with intra-pair differences in serum lipid and apolipoprotein levels. We report data for 1,720 monozygotic female twin-pairs from GenomEUtwin project with 2.5 million SNPs, imputed or genotyped, and measured serum lipid fractions for both twins. We found one locus associated with intra-pair differences in high-density lipoprotein cholesterol, rs2483058 in an intron of SRGAP2, where twins carrying the C allele are more sensitive to environmental factors (P = 3.98 × 10−8). We followed up the association in further genotyped monozygotic twins (N = 1,261), which showed a moderate association for the variant (P = 0.200, same direction of an effect). In addition, we report a new association on the level of apolipoprotein A-II (P = 4.03 × 10−8).
Multiple reports have identified variation in the GABRA2 gene as contributing to the genetic susceptibility to alcohol dependence. However, both the mechanism behind this association, and the range of alcohol-related phenotypes affected by variation in this gene, are currently undefined. Other data suggest that the risk of alcohol dependence is increased by relative insensitivity to alcohol's intoxicating effects. We have therefore tested whether GABRA2 variation is associated with variation in the subjective and objective effects of a standard dose of alcohol in humans. Data on responses to alcohol from the Alcohol Challenge Twin Study (Martin et al., 1985) have been tested against allelic and haplotype information obtained by typing 41 single-nucleotide polymorphisms in or close to the GABRA2 gene. Nominally significant allelic associations (p < .05, without correction for multiple testing) were found for body sway, motor coordination, pursuit rotor and arithmetical computation tasks, and for the personality dimension of Neuroticism. Because of the large number of phenotypes tested, these possibly significant findings will need to be confirmed in further studies.
In Australian twins participating in three different studies (1979–1996), the contribution of genetic and environmental influences to variation in resting systolic (SBP) and diastolic blood pressure (DBP) was studied. The sample consisted of 368 monozygotic and 335 dizygotic twin pairs with measurements for both individuals. Blood pressure measurements in two studies were available for 115 complete twin pairs, and 49 twin pairs had measurements in three studies. This allowed assessment of blood pressure tracking over an average period of 12 years in the age range of 23 to 45 years. Multivariate analyses showed significant heritability (h2) of blood pressure in all studies (SBP h2 = 19%–56%, DBP h2 = 37%–52%). In addition, the analyses showed that the blood pressure tracking was explained by the same set of genetic factors. These results replicate an earlier finding in Dutch twins that also showed stability of the contribution of genetic factors to blood pressure tracking.
Alcohol dependence symptoms and consumption measures were examined for stability and heritability. Data were collected from 12,045 individuals (5376 twin pairs, 1293 single twins) aged 19 to 90 years in telephone interviews conducted in three collection phases. Phases 1 and 2 were independent samples, but Phase 3 targeted families of smokers and drinkers from the Phase 1 and 2 samples. The stability of dependence symptoms and consumption was examined for 1158 individuals interviewed in both Phases 1 and 3 (mean interval = 11.0 years). For 1818 individuals interviewed in Phases 2 and 3 (mean interval = 5.5 years) the stability of consumption was examined. Heritability was examined for each collection phase and retest samples from the selected Phase 3 collection. The measures examined were a dependence score, based on DSM-IIIR and DSM-IV criteria for substance dependence, and a quantity × frequency measure. Measures were moderately stable, with test–retest correlations ranging from .58 to .61 for dependence and from .55 to .64 for consumption. However, the pattern of changes over time for dependence suggested that the measure may more strongly reflect recent than lifetime experience. Similar to previous findings, heritabilities ranged from .42 to .51 for dependence and from .31 to .51 for consumption. Consumption was significantly less heritable in the younger Phase 2 cohort (23–39 years) compared to the older Phase 1 cohort (28–90 years).
Plasma levels of lipoprotein(a) — Lp(a) — are associated with cardiovascular risk (Danesh et al., 2000) and were long believed to be influenced by the LPA locus on chromosome 6q27 only. However, a recent report of Broeckel et al. (2002) suggested the presence of a second quantitative trait locus on chromosome 1 influencing Lp(a) levels. Using a two-locus model, we found no evidence for an additional Lp(a) locus on chromosome 1 in a linkage study among 483 dizygotic twin pairs.
This study investigated the influence of genes and environment on the variation of apolipoprotein and lipid levels, which are important intermediate phenotypes in the pathways toward cardiovascular disease. Heritability estimates are presented, including those for apolipoprotein E and AII levels which have rarely been reported before. We studied twin samples from the Netherlands (two cohorts; n = 160 pairs, aged 13–22 and n = 204 pairs, aged 34–62), Australia (n = 1362 pairs, aged 28–92) and Sweden (n = 302 pairs, aged 42–88). The variation of apolipoprotein and lipid levels depended largely on the influences of additive genetic factors in each twin sample. There was no significant evidence for the influence of common environment. No sex differences in heritability estimates for any phenotype in any of the samples were observed. Heritabilities ranged from 0.48–0.87, with most heritabilities exceeding 0.60. The heritability estimates in the Dutch samples were significantly higher than in the Australian sample. The heritabilities for the Swedish were intermediate to the Dutch and the Australian samples and not significantly different from the heritabilities in these other two samples. Although sample specific effects are present, we have shown that genes play a major role in determining the variance of apolipoprotein and lipid levels in four independent twin samples from three different countries.
The genetic basis of cardiovascular disease (CVD) is complex and still largely elusive. Plasma lipid concentrations are well-established risk factors for cardiovascular disease (CVD), and have adult heritabilities ranging from 0.48 to 0.87. Estimates for adolescents are slightly higher (range 0.71 to 0.82). To identify loci affecting lipid concentrations across adolescence, we analyzed longitudinal lipid data in a sample of 134 monozygotic and 626 dizygotic twin pairs at ages twelve, fourteen and sixteen, and their siblings, from 760 Australian families. Univariate linkage analysis for each phenotype and time point was supplemented by multivariate analysis across the time points. A genome-wide association scan was also performed on a subset of the subjects (N = 441). The strongest linkage was seen for triglycerides on chromosome 6p24.3 (multivariate –log10p = 6.81; equivalent LOD = 6.13; p = 1.55 × 10–7). Significant linkage was also found for LDL cholesterol on chromosome 2q35 (multivariate –log10p = 5.59; equivalent LOD = 4.53; p = 2.57 × 10–6). In the association analysis, rs10503840 on 8p21.1 was significantly associated with total cholesterol levels at age fourteen (p = 8.24 × 10–7, estimated significance threshold 2.45 × 10–6). Association at p < 2.25 × 10–6 was also found between triglycerides at age 12 and rs10507266, in an intron of THRAP2 (MIM 608771) on 12q24.21; and between HDL-C at age 14 and rs10506325 in an intergenic region of 12q13.13. Suggestive evidence of association at ages twelve and fourteen was found between HDL-C and rs10492859 on 16q23 (p = 2.42 × 10–5 and 2.77 × 10–4, respectively). Further longitudinal genetic studies of cardiovascular risk factors, focused on critical periods of development or change, are needed.
Biochemical traits such as plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyltransferase (GGT) and uric acid are associated with obesity, and with risk of cardiovascular disease, metabolic syndrome and diabetes. Each is subject to genetic influences, but little is known about changes in genetic and environmental influences on these traits over time. We investigated the contribution of genetic and environmental influences to variation in these biochemical traits in adolescent twins and their nontwin siblings from 965 twin families. Twins were studied at ages 12, 14 and 16 years. Multivariate genetic models that included effects of age and sex were fitted to determine whether the same or different genetic or environmental factors influence each trait at different ages. Results showed that the genetic factors influencing AST, ALT, GGT and uric acid change over time during adolescence, and that the magnitude of these effects differs between males and females. The nonshared environment effects were generally time specific. There are developmental changes in genes affecting these traits during adolescence.
The consensus from published studies is that plasma lipids are each influenced by genetic factors, and that this contributes to genetic variation in risk of cardiovascular disease. Heritability estimates for lipids and lipoproteins are in the range .48 to .87, when measured once per study participant. However, this ignores the confounding effects of biological variation measurement error and ageing, and a truer assessment of genetic effects on cardiovascular risk may be obtained from analysis of longitudinal twin or family data. We have analyzed information on plasma high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides, from 415 adult twins who provided blood on two to five occasions over 10 to 17 years. Multivariate modeling of genetic and environmental contributions to variation within and across occasions was used to assess the extent to which genetic and environmental factors have long-term effects on plasma lipids. Results indicated that more than one genetic factor influenced HDL and LDL components of cholesterol, and triglycerides over time in all studies. Nonshared environmental factors did not have significant long-term effects except for HDL. We conclude that when heritability of lipid risk factors is estimated on only one occasion, the existence of biological variation and measurement errors leads to underestimation of the importance of genetic factors as a cause of variation in long-term risk within the population. In addition our data suggest that different genes may affect the risk profile at different ages.
The aim of this study is to characterize the relationship between major depression and the metabolic syndrome in a large community based sample of Australian men and women aged 26–90 years. A lifetime history of major depression was assessed by telephone interview following the DSM–III-R. A current history of metabolic syndrome was assessed following the United States National Cholesterol Education Program Adult Treatment Panel III (NCEP AP-III) guidelines 1 to 3 years later. Logistic regression was used to estimate the association between depression and the metabolic syndrome, and its component criteria, controlling for age, sex and alcohol dependence. There was no association between a lifetime history of major depression and the presence of the metabolic syndrome. There was a weak association between depression and low high-density lipoprotein cholesterol but not with other component criteria of the metabolic syndrome. Despite calls for interventions directed at depression to reduce the onset of the metabolic syndrome there are important failures to replicate in large samples such as this, no consensus regarding the threshold at which depression may pose a significant risk even allowing for heterogeneity across populations, and no consensus regarding confounders that may explain inter-study differences. The absence of any dosage effect of depression on the associated risk for the metabolic syndrome in other unselected samples does not support a direct causal relationship. The call for intervention studies on the basis of the currently published evidence base is unwarranted.
Birthweight affects neonatal mortality and morbidity and has been used as a marker of foetal undernutrition in studies of prenatal effects on adult characteristics. It is potentially influenced by genetic and environmental influences on the mother, and effects of foetal genotype, which is partially derived from the maternal genotype. Interpretations of variation in birthweight and associated characteristics as being due to prenatal environment ignore other possible modes of materno-foetal transmission. Subjects were adult twins recruited through the Australian Twin Registry, aged 17 to 87 years, and the sample comprised 1820 men and 4048 women. Twins reported their own birthweight as part of a health questionnaire. Body Mass Index (BMI) was calculated from self-reports of height and weight. Correlations between co-twins' birthweights were high for both monozygotic (r = 0.77) and dizygotic (r = 0.67) pairs, leading to substantial estimates of shared environmental effects (56% of variance) with significant additive genetic (23%) and non-shared environmental (21%) components. Adult BMI was mainly influenced by genetic factors, both additive (36% of variance) and nonadditive (35%). The correlation between birthweight and BMI was positive, in that heavier babies became on average more obese adults. A bivariate model of birthweight and adult BMI showed significant positive genetic (rg = 0.16, p = 0.005) and environmental (re = 0.08, p = 0.000011) correlations. Intra-uterine environmental or perinatal influences shared by cotwins exercise a strong influence on birthweight, but the factors which affect both birthweight and adult BMI are partly genetic and partly non-shared environmental.
Despite the decline in coronary heart disease in many European countries, the disease remains an enormous public health problem. Although we know a great deal about environmental risk factors for coronary heart disease, a heritable component was recognized a long time ago. The earliest and best known examples of how our genetic constitution may determine cardiovascular risk relate to lipoprotein(a), familial hypercholesterolaemia and apolipoprotein E. In the past 20 years a fair number of polymorphisms assessed singly have shown strong associations with the disease but most are subject to poor repeatability. Twins constitute a compelling natural experiment to establish the genetic contribution to coronary heart disease and its risk factors. GenomEUtwin, a recently funded Framework 5 Programme of the European Community, affords the opportunity of comparing the heritability of risk factors in different European Twin Registries. As an illustration we present the heritabilities of systolic and diastolic blood pressure, based on data from over 4000 twin pairs from six different European countries and Australia. Heritabilities for systolic blood pressure are between 52 and 66% and for diastolic blood pressure between 44 and 66%. There is no evidence of sex differences in heritability estimates and very little to no evidence for a significant contribution of shared family environment. A non-twin based prospective case/cohort study of coronary heart disease and stroke (MORGAM) will allow hypotheses relating to cardiovascular disease, generated in the twin cohorts, to be tested prospectively in adult populations. Twin studies have also contributed to our understanding of the life course hypothesis, and GenomEUtwin has the potential to add to this.
Plasma lipids such as high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol and triglyceride levels contribute to variation in the risk of cardiovascular disease. The early stages of atherosclerosis in childhood have also been associated with changes in triglycerides, LDL and HDL. Heritability estimates for lipids and lipoproteins for adolescents are in the range .71 to .82, but little is known about changes of genetic and environmental influences over time in adolescence. We have investigated the contribution of genetic and environmental influences to variation in lipids in adolescent twins and their nontwin siblings using longitudinal twin and family data. Plasma HDL and LDL cholesterol, total cholesterol and triglycerides data from 965 twin pairs at 12, 14 and 16 years of age and their siblings have been analyzed. Longitudinal genetic models that included effects of age, sex and their interaction were fitted to assess whether the same or different genes influence each trait at different ages. Results suggested that more than one genetic factor influences HDL, LDL, total cholesterol and triglycerides over time at ages 12, 14 and 16 years. There was no evidence of shared environmental effects except for HDL and little evidence of long-term nonshared environmental effects was found. Our study suggested that there are developmental changes in the genes affecting plasma lipid concentrations across adolescence.
The choice of where to live would appear to be determined by a combination of economic constraints and personal preferences. We have tested how far this choice is affected by the continuing effects of the environment shared within families, and genetic variation between people, using data from twin studies conducted in Australia. The addresses provided by study participants were categorized as urban, suburban and nonurban, and data were analyzed in three adult age groups. There were significant effects of both shared environment and genes, and the balance between them was affected by both sex and age. Shared environment accounted for some 50% of variation in the youngest group, but only about 10% in the oldest. As shared environmental effects decreased, additive genetic effects increased. These results have implications for internal migration of people within countries and, over the long term, for gene flow within and between populations. They may also be pertinent to the different prevalences of certain psychiatric diseases between city and country locations. Comparisons between countries with different demography are needed to confirm and further characterize these effects.