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1.  Lipoprotein Particle Profiles Mark Familial and Sporadic Human Longevity 
PLoS Medicine  2006;3(12):e495.
Genetic and biochemical studies have indicated an important role for lipid metabolism in human longevity. Ashkenazi Jewish centenarians and their offspring have large low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles as compared with control individuals. This profile also coincided with a lower prevalence of disease. Here, we investigate whether this observation can be confirmed for familial longevity in an outbred European population and whether it can be extended to sporadic longevity in the general population.
Methods and Findings
NMR-measured lipoprotein profiles were analyzed in 165 families from the Leiden Longevity Study, consisting of 340 long-lived siblings (females >91 y, males >89 y), 511 of their offspring, and 243 partners of the offspring. Offspring had larger (21.3 versus 21.1 nm; p = 0.020) and fewer (1,470 versus 1,561 nmol/l; p = 0.011) LDL particles than their same-aged partners. This effect was even more prominent in the long-lived siblings (p < 10−3) and could be pinpointed to a reduction specifically in the concentration of small LDL particles. No differences were observed for HDL particle phenotypes. The mean LDL particle sizes in 259 90-y-old singletons from a population-based study were similar to those in the long-lived siblings and thus significantly larger than in partners of the offspring, suggesting that the relevance of this phenotype extends beyond familial longevity. A low concentration of small LDL particles was associated with better overall health among both long-lived siblings (p = 0.003) and 90-y-old singletons (p = 0.007).
Our study indicates that LDL particle profiles mark both familial and sporadic human longevity already in middle age.
Offspring of families from the Leiden Longevity Study had larger and fewer LDL particles than same-aged partners, suggesting that even in middle age LDL particle profiles are associated with longevity.
Editors' Summary
It is not clear why some people go on to live longer than others do. Some studies have shown that close relatives of long-lived people are themselves more likely to live for a long time; these findings suggest that there is probably a genetic basis for long life. However, the actual mechanisms involved have not yet been worked out. Some genes coding for proteins involved in fat metabolism, such as APOE, APOB, and CETP, have been associated with long life, suggesting a link between the way fat gets metabolized and the aging process. One study that supports this idea found that the children of 100-year-old people had larger lipoprotein particles (assemblies of proteins and fats that carry cholesterol and triglycerides in the blood) than similarly aged control individuals. However, studies such as this are very prone to “false positive” findings and therefore need to be backed up by confirmatory evidence. In addition, the previous study was performed in a very specific population (Ashkenazi Jewish people), and it is important to find out whether the findings are also true in other populations.
Why Was This Study Done?
The research group carrying out this study wanted to address several distinct questions to do with the genetics of aging. Firstly, they wanted to see if they could confirm previous findings associating large lipoprotein particles with longer life, but looking at people who were more representative of the general European population and not from a genetically isolated population. Secondly, they wanted to see whether this association applied to only long-lived people whose family members were also long-lived, or to long-lived people in general. Finally, they wanted to find out if the large lipoprotein particles were associated with better health.
What Did the Researchers Do and Find?
In the study, the researchers looked at long-lived people from across The Netherlands whose relatives were also long-lived. For this, they recruited 340 men aged over 89 and women aged over 91 into the study, all of whom had at least one similarly long-lived sister or brother. Their children (511 individuals), and the partners of their children (243 people), were also recruited into the study, with the partners acting as “controls.” The researchers also studied 259 people who had just turned 90 years old; these people were included to see whether particular characteristics of lipoproteins existed in long-lived people whose longevity did not run in families. All the participants gave blood samples, and the researchers then measured the size and amount of different lipoprotein particles in these samples. Two types of lipoprotein particles were looked at: low-density lipoprotein (LDL, often termed “bad cholesterol”) and high-density lipoprotein (HDL, sometimes called “good cholesterol”). The researchers found that the children from the long-lived people had larger and fewer LDL particles than their partners (the “control” individuals) just like their long-lived parents. Thus even though the children were not long-lived themselves, LDL particles marked the fact that they have a higher chance of becoming long-lived in the future. Similar changes in LDL particles were found for long-lived people whose relatives were not also long-lived. Interestingly, simply the level of cholesterol—the classical risk factor for cardiovascular disease—did not appear to play a role. Thus it seems that it is not the amount of cholesterol that is important in longevity but how it is packaged. Better health status was also associated with a lower proportion of small LDL particles in the blood, supporting these findings. No characteristics of the HDL particles seemed to be associated with longevity.
What Do These Findings Mean?
These findings confirm those from a previous study in Ashkenazi Jewish people that suggested that the size of LDL particles in the blood was associated with long life. The nature of this association is not clear; some studies indicated that small LDL particles increase the risk of cardiovascular disease but small LDL particles may also be harmless themselves and reflect the efficiency of other processes causally related to aging.
Additional Information.
Please access these Web sites via the online version of this summary at
Wikipedia chapter on senescence (biology of aging) (note that Wikipedia is a free Internet encyclopedia that anyone can edit)
US National Institute on Aging provides information on healthy aging, details of publicly funded research into aging, and other resources for the public
Help the Aged information on research into aging
PMCID: PMC1716190  PMID: 17194192
2.  Genetic and environmental variation in serum lipoproteins in relation to coronary heart disease 
Journal of Medical Genetics  1979;16(2):85-100.
Variation in the serum concentration of VLDL, IDL, LDL, and HDL was studied in (a) 192 survivors of myocardial infarction under the age of 50 living in the north-east of Scotland; (b) 250 relatives, mostly first degree; and (c) 259 unrelated individuals, comprising mostly spouses and their relatives.
The biochemical characterisation of the lipids, which were separated by preparative ultracentrifugation, included (a) determination of total serum cholesterol and triglyceride; and (b) determination of the content of cholesterol in the four fractions, and also of triglyceride in the VLDL fraction.
In male survivors of infarction there is a significant negative regression of VLDL and a significant positive regression of HDL on peak aspartate aminotransferase activity in blood samples taken within 24 hours of the incident. In later samples correlations were not evident.
Serum lipoprotein concentrations have been compared in samples taken at different times after the incident. The average value of samples taken within 24 hours is similar to the mean scores for LDL and VLDL of repeat samples taken, on average, 9 months later.
The incidence of hyperlipidaemia in samples taken within 24 hours of the infarction is about the same for total cholesterol and triglyceride and LDL or VLDL. Respectively, 18·3%, 16·1%, and 7·5% of the survivors exceed the 90th centile value for either LDL, VLDL, or both fractions, while, for the 95th centile limit, the corresponding figures are 8·6%, 9·7%, and 2·2%.
In samples taken within 24 hours of the incident, the LDL concentration is, on average, 20 to 30% higher, and the VLDL concentration 50 to 60% higher, than the controls. The corresponding HDL difference in males, though negative, is trivial and statistically insignificant, but in females the difference is greater and significantly so.
VLDL levels are substantially increased in regular cigarette smokers in both sexes, especially in males. HDL levels tend to be lower, though not significantly so. The frequency of persons who are or have been regular cigarette smokers is higher in index cases than in controls.
Correlation analysis of individual variation of controls and index case relatives indicates a substantial level of independence between the major lipoprotein fractions. There is no correlation between LDL and HDL. There are positive correlations between VLDL, IDL, and LDL, though when IDL is held constant by multiple regression, the correlation between VLDL and LDL is removed. There is a low but consistent negative correlation between VLDL and HDL cholesterol.
About a quarter of the variance of VLDL in males is accounted for by multiple regression on measures of body fatness, that is, relative weight and subscapular skinfold thickness. In females only about 10% of the variance is thus accounted for, and only in males do LDL levels show correlated changes with fatness. There are no significant differences for either relative body weight or subscapular skinfold thickness between the means of first degree relatives of survivors of infarction and controls.
The concentrations of VLDL and LDL in first degree relatives of survivors of infarction are significantly higher than the control means. HDL shows no significant difference.
The evidence for genetic variation in serum lipoprotein is based on the polygenic model and the analysis of the correlation between parents and offspring and the correlation between sibs. From the pooled regression on single parents, heritabilities for HDL, LDL, and VLDL work out at 0·67 ± 0·21, 0·36 ± 0·18, and 0·23 ± 0.20, respectively. The lower heritability of VLDL is consistent with the variance of repeat measurements on the same control individuals, which is much higher for VLDL than for LDL or HDL. The high correlation between VLDL and measures of fatness, for which heritability estimates are statistically insignificant, as well as the association between raised VLDL concentration and smoking, also provide confirmatory evidence of the major importance of non-genetic causes in the variation of VLDL.
The results are discussed in relation to the origin of the effects of smoking, variation in proneness to coronary disease, and the biological significance of differences in HDL concentration.
PMCID: PMC1012732  PMID: 458839
3.  Genetic and Environmental Influences on the Familial Transmission of Externalizing Disorders in Adoptive and Twin Offspring 
JAMA psychiatry (Chicago, Ill.)  2013;70(10):1076-1083.
Twin-family studies have shown that parent-child resemblance on substance use disorders and antisocial behavior can be accounted for by the transmission of a general liability to a spectrum of externalizing disorders. Most studies, however, include only biological parents and offspring, which confound genetic and environmental transmission effects.
Examine the family transmission of externalizing disorders among both adoptive (who are genetically unrelated) and biological relatives to better distinguish genetic and environmental mechanisms of transmission.
Family study design wherein each family included the mother, father, and two offspring, including monozygotic twin, dizygotic twin, non-twin biological and adoptive offspring. Structural equation modeling was used to estimate family transmission effects and their genetic and environmental influences.
Participants were recruited from the community and assessed at a university laboratory.
1590 families with biological offspring and 409 families with adoptive offspring. Offspring participants were young adults (mean age = 26.2 years).
Main outcome measures
Symptom counts of conduct disorder, adult antisocial behavior, and alcohol, nicotine, and drug dependence.
There was a medium effect for the transmission of the general externalizing liability for biological parents (r = 0.27-0.30), but not for adoptive parents (r = 0.03-0.07). In contrast, adoptive siblings exhibited significant similarity on the general externalizing liability (r = 0.21). Biometric analyses revealed the general externalizing liability was highly heritable (a2 = 0.61), but also exhibited significant shared environmental influences (c2 = 0.20).
Parent-child resemblance for substance use disorders and antisocial behavior is primarily due to the genetic transmission of a general liability to a spectrum of externalizing disorders. Including adoptive siblings revealed a greater role of shared environmental influences on the general externalizing liability than previously detected in twin studies, and indicates sibling rather than parent-child similarity indexes important environmental risk factors for externalizing disorders.
PMCID: PMC3790867  PMID: 23965950
4.  Human metabolic profiles are stably controlled by genetic and environmental variation 
A comprehensive variation map of the human metabolome identifies genetic and stable-environmental sources as major drivers of metabolite concentrations. The data suggest that sample sizes of a few thousand are sufficient to detect metabolite biomarkers predictive of disease.
We designed a longitudinal twin study to characterize the genetic, stable-environmental, and longitudinally fluctuating influences on metabolite concentrations in two human biofluids—urine and plasma—focusing specifically on the representative subset of metabolites detectable by 1H nuclear magnetic resonance (1H NMR) spectroscopy.We identified widespread genetic and stable-environmental influences on the (urine and plasma) metabolomes, with (30 and 42%) attributable on average to familial sources, and (47 and 60%) attributable to longitudinally stable sources.Ten of the metabolites annotated in the study are estimated to have >60% familial contribution to their variation in concentration.Our findings have implications for the design and interpretation of 1H NMR-based molecular epidemiology studies. On the basis of the stable component of variation quantified in the current paper, we specified a model of disease association under which we inferred that sample sizes of a few thousand should be sufficient to detect disease-predictive metabolite biomarkers.
Metabolites are small molecules involved in biochemical processes in living systems. Their concentration in biofluids, such as urine and plasma, can offer insights into the functional status of biological pathways within an organism, and reflect input from multiple levels of biological organization—genetic, epigenetic, transcriptomic, and proteomic—as well as from environmental and lifestyle factors. Metabolite levels have the potential to indicate a broad variety of deviations from the ‘normal' physiological state, such as those that accompany a disease, or an increased susceptibility to disease. A number of recent studies have demonstrated that metabolite concentrations can be used to diagnose disease states accurately. A more ambitious goal is to identify metabolite biomarkers that are predictive of future disease onset, providing the possibility of intervention in susceptible individuals.
If an extreme concentration of a metabolite is to serve as an indicator of disease status, it is usually important to know the distribution of metabolite levels among healthy individuals. It is also useful to characterize the sources of that observed variation in the healthy population. A proportion of that variation—the heritable component—is attributable to genetic differences between individuals, potentially at many genetic loci. An effective, molecular indicator of a heritable, complex disease is likely to have a substantive heritable component. Non-heritable biological variation in metabolite concentrations can arise from a variety of environmental influences, such as dietary intake, lifestyle choices, general physical condition, composition of gut microflora, and use of medication. Variation across a population in stable-environmental influences leads to long-term differences between individuals in their baseline metabolite levels. Dynamic environmental pressures lead to short-term fluctuations within an individual about their baseline level. A metabolite whose concentration changes substantially in response to short-term pressures is relatively unlikely to offer long-term prediction of disease. In summary, the potential suitability of a metabolite to predict disease is reflected by the relative contributions of heritable and stable/unstable-environmental factors to its variation in concentration across the healthy population.
Studies involving twins are an established technique for quantifying the heritable component of phenotypes in human populations. Monozygotic (MZ) twins share the same DNA genome-wide, while dizygotic (DZ) twins share approximately half their inherited DNA, as do ordinary siblings. By comparing the average extent of phenotypic concordance within MZ pairs to that within DZ pairs, it is possible to quantify the heritability of a trait, and also to quantify the familiality, which refers to the combination of heritable and common-environmental effects (i.e., environmental influences shared by twins in a pair). In addition to incorporating twins into the study design, it is useful to quantify the phenotype in some individuals at multiple time points. The longitudinal aspect of such a study allows environmental effects to be decomposed into those that affect the phenotype over the short term and those that exert stable influence.
For the current study, urine and blood samples were collected from a cohort of MZ and DZ twins, with some twins donating samples on two occasions several months apart. Samples were analysed by 1H nuclear magnetic resonance (1H NMR) spectroscopy—an untargeted, discovery-driven technique for quantifying metabolite concentrations in biological samples. The application of 1H NMR to a biological sample creates a spectrum, made up of multiple peaks, with each peak's size quantitatively representing the concentration of its corresponding hydrogen-containing metabolite.
In each biological sample in our study, we extracted a full set of peaks, and thereby quantified the concentrations of all common plasma and urine metabolites detectable by 1H NMR. We developed bespoke statistical methods to decompose the observed concentration variation at each metabolite peak into that originating from familial, individual-environmental, and unstable-environmental sources.
We quantified the variability landscape across all common metabolite peaks in the urine and plasma 1H NMR metabolomes. We annotated a subset of peaks with a total of 65 metabolites; the variance decompositions for these are shown in Figure 1. Ten metabolites' concentrations were estimated to have familial contributions in excess of 60%. The average proportion of stable variation across all extracted metabolite peaks was estimated to be 47% in the urine samples and 60% in the plasma samples; the average estimated familiality was 30% for urine and 42% for plasma. These results comprise the first quantitative variation map of the 1H NMR metabolome. The identification and quantification of substantive widespread stability provides support for the use of these biofluids in molecular epidemiology studies. On the basis of our findings, we performed power calculations for a hypothetical study searching for predictive disease biomarkers among 1H NMR-detectable urine and plasma metabolites. Our calculations suggest that sample sizes of 2000–5000 should allow reliable identification of disease-predictive metabolite concentrations explaining 5–10% of disease risk, while greater sample sizes of 5000–20 000 would be required to identify metabolite concentrations explaining 1–2% of disease risk.
1H Nuclear Magnetic Resonance spectroscopy (1H NMR) is increasingly used to measure metabolite concentrations in sets of biological samples for top-down systems biology and molecular epidemiology. For such purposes, knowledge of the sources of human variation in metabolite concentrations is valuable, but currently sparse. We conducted and analysed a study to create such a resource. In our unique design, identical and non-identical twin pairs donated plasma and urine samples longitudinally. We acquired 1H NMR spectra on the samples, and statistically decomposed variation in metabolite concentration into familial (genetic and common-environmental), individual-environmental, and longitudinally unstable components. We estimate that stable variation, comprising familial and individual-environmental factors, accounts on average for 60% (plasma) and 47% (urine) of biological variation in 1H NMR-detectable metabolite concentrations. Clinically predictive metabolic variation is likely nested within this stable component, so our results have implications for the effective design of biomarker-discovery studies. We provide a power-calculation method which reveals that sample sizes of a few thousand should offer sufficient statistical precision to detect 1H NMR-based biomarkers quantifying predisposition to disease.
PMCID: PMC3202796  PMID: 21878913
biomarker; 1H nuclear magnetic resonance spectroscopy; metabolome-wide association study; top-down systems biology; variance decomposition
5.  Segregation analysis of apolipoprotein A1 levels in families of adolescents: A community-based study in Taiwan 
BMC Genetics  2006;7:4.
Apolipoprotein (Apo) A1 is a protective factor for cardiovascular events. This study aimed to perform complex segregation analyses of Apo A1 levels in families of adolescents systematically ascertained from the junior high school students in a rural community. Both siblings and parents of the adolescent probands were recruited for the study. Apo A1 concentrations were measured by turbidimetric immunoassay methods. After adjustment for gender, age, body mass index, smoking and drinking status, residual values of Apo A1 were subjected to subsequent analyses.
Significant mother-father and parent-offspring correlations were found. Commingling analyses indicated that a four-component distribution model was needed to account for the Apo A1 variation. Segregation analysis using regressive models revealed that the best-fit model of Apo A1 was a model of environmental effect plus familial correlation (heritability = 23.9%), in which a significant mother-father correlation existed. Models containing major gene effect could be rejected.
These results suggest that variations of Apo A1 levels in the normal range, especially during adolescence, are likely to be influenced by multiple factors without significant contribution from major genes.
PMCID: PMC1360683  PMID: 16423305
6.  A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study 
BMC Medical Genetics  2007;8(Suppl 1):S17.
Blood lipid levels including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are highly heritable. Genome-wide association is a promising approach to map genetic loci related to these heritable phenotypes.
In 1087 Framingham Heart Study Offspring cohort participants (mean age 47 years, 52% women), we conducted genome-wide analyses (Affymetrix 100K GeneChip) for fasting blood lipid traits. Total cholesterol, HDL-C, and TG were measured by standard enzymatic methods and LDL-C was calculated using the Friedewald formula. The long-term averages of up to seven measurements of LDL-C, HDL-C, and TG over a ~30 year span were the primary phenotypes. We used generalized estimating equations (GEE), family-based association tests (FBAT) and variance components linkage to investigate the relationships between SNPs (on autosomes, with minor allele frequency ≥10%, genotypic call rate ≥80%, and Hardy-Weinberg equilibrium p ≥ 0.001) and multivariable-adjusted residuals. We pursued a three-stage replication strategy of the GEE association results with 287 SNPs (P < 0.001 in Stage I) tested in Stage II (n ~1450 individuals) and 40 SNPs (P < 0.001 in joint analysis of Stages I and II) tested in Stage III (n~6650 individuals).
Long-term averages of LDL-C, HDL-C, and TG were highly heritable (h2 = 0.66, 0.69, 0.58, respectively; each P < 0.0001). Of 70,987 tests for each of the phenotypes, two SNPs had p < 10-5 in GEE results for LDL-C, four for HDL-C, and one for TG. For each multivariable-adjusted phenotype, the number of SNPs with association p < 10-4 ranged from 13 to 18 and with p < 10-3, from 94 to 149. Some results confirmed previously reported associations with candidate genes including variation in the lipoprotein lipase gene (LPL) and HDL-C and TG (rs7007797; P = 0.0005 for HDL-C and 0.002 for TG). The full set of GEE, FBAT and linkage results are posted at the database of Genotype and Phenotype (dbGaP). After three stages of replication, there was no convincing statistical evidence for association (i.e., combined P < 10-5 across all three stages) between any of the tested SNPs and lipid phenotypes.
Using a 100K genome-wide scan, we have generated a set of putative associations for common sequence variants and lipid phenotypes. Validation of selected hypotheses in additional samples did not identify any new loci underlying variability in blood lipids. Lack of replication may be due to inadequate statistical power to detect modest quantitative trait locus effects (i.e., <1% of trait variance explained) or reduced genomic coverage of the 100K array. GWAS in FHS using a denser genome-wide genotyping platform and a better-powered replication strategy may identify novel loci underlying blood lipids.
PMCID: PMC1995614  PMID: 17903299
7.  Familial aggregation of components of the multiple metabolic syndrome in the Framingham Heart and Offspring Cohorts: Genetic Analysis Workshop Problem 1 
BMC Genetics  2003;4(Suppl 1):S94.
The multiple metabolic syndrome is defined by a clustering of risk factors for cardiovascular disease. We sought to evaluate the familial correlations of the components of the syndrome using data from the Framingham Heart Study original and offspring cohorts as provided for the Genetic Analysis Workshop 13. Measures of plasma cholesterol (total and HDL), body mass index (BMI), and systolic blood pressure were used from selected calendar years of exams. Familial correlations were calculated using FCOR in S.A.G.E.
The sibling correlations were relatively high for all measures and exams, from 0.17 for systolic blood pressure to 0.27 for HDL cholesterol. The parent-child correlations were very similar, except for systolic blood pressure. The avuncular correlations were much smaller and the cousin correlations were even smaller. For HDL cholesterol the avuncular correlation was half the sibling correlation and the cousin correlation was half that again. Spousal correlations ranged from 0.07 for systolic blood pressure to 0.34 for BMI. Correlations were somewhat lower from 1984 to 1987 examinations than from 1971 to 1975 examinations, except for spousal correlations for systolic blood pressure and BMI.
The results of the family pair correlations are suggestive of genetic determinants of lipid levels and BMI. These components have been shown to be predictive of cardiovascular disease as well as diabetes. Genes in common with each of the components might also influence development of cardiovascular disease and diabetes, both complex diseases.
PMCID: PMC1866535  PMID: 14975162
8.  The Familial Aggregation of Cigarette Smoking in Kish, Iran 
Based on WHO reports, smoking is an epidemic in developing countries. One of important issues about this behavior is its distribution pattern in family members. The main purpose of this study was to evaluate if cigarette smoking had a tendency to cluster or aggregate in the families and what the determinants were.
Using a multi-stage random cluster sampling approach, a household survey was conducted in Kish Island in 2009. We used the Alternating Logistic Regressions algorithm to model to show the familial aggregation.
The odds ratio for the aggregation of cigarette smoking between family members was 1.63 (1.29-2.06) which increased to 1.96 (1.50-2.55) after adjustment for demographic factors. There was no significant correlation between siblings' cigarette smoking nor was between spouses but the pairwise odds ratio for parents offspring was significant. In other words, cigarette smoking in at least one of the parents increased the odds of being a smoker in offspring significantly.
The study showed that the smoking behavior aggregated in families significantly. The inter-parent offspring aggregation was the main component of the familial aggregation. Higher education and age-gender interaction were determinants of smoking in the families. The programs for prevention and cessation of this behavior in the community might be more successful if they were designed in a family-based rather than an individual-based approach.
PMCID: PMC3372035  PMID: 22737572
Smoking; Familial aggregation; Pairwise odds ratio; Family-based methods
9.  Family history as a risk factor for recurrent hospitalization for lone atrial fibrillation: a nationwide family study in Sweden 
Although the heritability of atrial fibrillation (AF) has been determined, the relevance of family history of AF for the likelihood of recurrent hospitalization for AF is unknown. The aim of this nationwide study was to determine whether family history of AF is a risk factor of recurrent hospitalization for lone AF (LAF), i.e., AF with unknown etiology. The familial risk for first time LAF hospitalization was also determined and compared to the risk of recurrent hospitalization for LAF.
We examined whether family history of AF is a risk factor for recurrent hospitalization for LAF in the whole Swedish population. We linked Multigeneration Register data on individuals aged 0–60 years to Hospital Discharge Register data for the period 1987–2009 to compare LAF recurrent hospitalization risk among individuals with and without parental or sibling history of AF. We calculated hazard ratios (HRs) to determine the familial HR of recurrent hospitalization for LAF. Odds ratios (OR) were calculated for familial risk of first time LAF hospitalization.
The risk of recurrent LAF hospitalization was 1.23 (95% CI 1.17-1.30) for individuals with affected parents compared to 1.30 (95% CI 1.22-1.38) for those with affected siblings. After 10 years of follow up 50% of those without and 60% of those with family history had recurrent hospitalization for LAF. The risk of recurrent LAF hospitalization in individuals with two affected parents was 1.65 (95% CI 1.44-1.90). There was an interaction between age and family history, with family history having a weaker effect on LAF hospitalization risk in older age groups. The OR for first time LAF hospitalization was 2.08 (95% CI 2.02-2.15) for offspring with affected parents and 3.23 (95% CI 3.08-3.39) for individuals with affected siblings.
Family history of AF is a novel risk factor for recurrent LAF hospitalization. The higher recurrence hospitalization risk in multiplex families and younger individuals suggests a genetic contribution. However, the familial risk for recurrent LAF hospitalization was much lower than the risk for first time LAF hospitalization, suggesting that familial and possibly genetic factors are more important for first time LAF hospitalization than recurrent LAF hospitalization.
PMCID: PMC3523073  PMID: 23227964
Atrial fibrillation; Family history; Risk factors; Genetics
10.  Genetic epidemiology of cardiometabolic risk ractors and their clustering patterns in Mexican American children and adolescents: The SAFARI Study 
Human genetics  2013;132(9):10.1007/s00439-013-1315-2.
Pediatric metabolic syndrome (MS) and its cardiometabolic components (MSCs) have become increasingly prevalent, yet little is known about the genetics underlying MS risk in children. We examined the prevalence and genetics of MS-related traits among 670 non-diabetic Mexican American (MA) children and adolescents, aged 6–17 years (49 % female), who were participants in the San Antonio Family Assessment of Metabolic Risk Indicators in Youth (SAFARI) study. These children are offspring or biological relatives of adult participants from three well-established Mexican American family studies in San Antonio, Texas, at increased risk of type 2 diabetes. MS was defined as ≥ 3 abnormalities among 6 MSC measures: waist circumference, systolic and/or diastolic blood pressure, fasting insulin, triglycerides, HDL-cholesterol, and fasting and/or 2-h OGTT glucose. Genetic analyses of MS, number of MSCs (MSC-N), MS factors, and bivariate MS traits were performed. Overweight/obesity (53 %), pre-diabetes (13 %), acanthosis nigricans (33 %), and MS (19 %) were strikingly prevalent, as were MS components, including abdominal adiposity (32 %) and low HDL-cholesterol (32 %). Factor analysis of MS traits yielded three constructs: adipo-insulin-lipid, blood pressure, and glucose factors, and their factor scores were highly heritable. MS itself exhibited 68 % heritability. MSC-N showed strong positive genetic correlations with obesity, insulin resistance, inflammation, and acanthosis nigricans, and negative genetic correlation with physical fitness. MS trait pairs exhibited strong genetic and/or environmental correlations. These findings highlight the complex genetic architecture of MS/MSCs in MA children, and underscore the need for early screening and intervention to prevent chronic sequelae in this vulnerable pediatric population.
PMCID: PMC3845827  PMID: 23736306
11.  Pleiotropic effects on subclasses of HDL, adiposity and glucose metabolism in adult Alaskan Eskimos 
The aim of the present study was to analyze the heritability and the presence of pleiotropic effects on subfractions of high density lipoproteins (HDLs) as measured by nuclear magnetic resonance (NMR), parameters for adiposity and glucose metabolism in adult Alaskan Eskimos. The present family study included 1214 adult Alaskan Eskimos (537 male/677 female). Body weight, height, circumferences, selected skinfolds and blood pressure were measured in all participants. Blood samples were collected under fasting conditions for isolation of plasma. Glucose, insulin, subclasses and size of lipoproteins, triglycerides, total and HDL cholesterol and lipoprotein (a) were measured in plasma. HbA1c was measured in total blood. Univariate and bivariate quantitative genetic analyses were conducted between HDL subclasses and size and the anthropometric and biochemical measures using the variance decomposition approach. Variation in all the analyzed traits exhibits a significant genetic component. Heritabilities ranged between 0.18 ± 0.11 for LDL2 (intermediate) to 0.89 ± 0.07 for small HDL. No common genetic effects were found on the HDL subclasses (small, intermediate and large). Small HDL particles were genetically correlated with LDL particles and HbA1c. Negative genetic correlations were observed between intermediate and large HDL subfractions and HDL size and measures of adiposity, LDL and parameters for glucose metabolism (HbA1, insulin). These observations confirm the presence of possible pleiotropic effects on HDL, adiposity and cardiovascular risk factors and provide novel insight on the relationship between HDL subclasses, adiposity and glucose regulation.
PMCID: PMC3461838  PMID: 19950191
12.  Age moderates non-genetic influences on the initiation of cannabis use: a twin-sibling study in Dutch adolescents and young adults 
Addiction (Abingdon, England)  2011;106(9):1658-1666.
To examine the heritability of cannabis initiation, the influence of a possible twin specific environment and the influence of age on the effects of genes and environment in Dutch adolescents and young adults.
Genetic structural equation modeling was used to partition the variance in the liability to cannabis initiation into genetic and environmental components.
All participants were registered with the Netherlands Twin Register.
A total of 6,208 twins (age 13-20) and 1,545 siblings (age 11 -25) from 3,503 families participated in this study.
Self-reported cannabis use was prospectively assessed with the Dutch Health Behavior Questionnaire.
At the median age of the sample (16.5) genetic factors explained 40% of the individual differences in liability to cannabis initiation. Twins resembled each other more than non-twin siblings which could not be attributed to the age difference between non-twin siblings. Environmental influences increased with age. This increase applied to environmental factors shared by twins (47% of the variance), environmental factors shared by twins and siblings (24%) and environmental factors unique to an individual (13%).
The heritability of the liability for cannabis initiation is higher in adolescents than in young adults due to a larger contribution of environmental factors in young adults. This is mostly due to environmental factors only shared by twins and those shared by all offspring growing up in the same family but the contribution of environmental factors specific to individuals is also larger in young adults.
PMCID: PMC4001801  PMID: 21489006
13.  Familial aggregation of circulating c-reactive protein in polycystic ovary syndrome 
What is the heritability of C-reactive protein (CRP) levels in women with polycystic ovary syndrome (PCOS) and their first-degree relatives?
Women with PCOS and their siblings are more likely to have elevated CRP levels when both of their parents have elevated CRP. This PCOS family-based study indicates that CRP levels are likely a heritable trait.
Previous studies have established that an elevated blood level of CRP is variably present in women with PCOS, and may be present independent of metabolic status.
A familial based phenotyping study consisting of 81 families comprised of PCOS patients and their first-degree relatives for 305 subjects.
Study conducted at an academic health center. An elevated CRP level was defined as >28.6 nmol/l. To account for familial clustering, generalized estimating equations with a logit link were used to model the association between elevated CRP levels in patients with PCOS and their siblings with their parental group (A = neither parent with elevated CRP; B = one parent with elevated CRP; C= both parents with elevated CRP), adjusting for gender, age and BMI of the offspring. We did additional heritability analyses by using a variance component estimation method for CRP levels, adjusting for sex, age and BMI.
We observed elevated CRP levels in 94% of the offspring in group C, 45% in group B and 10% in group A after adjusting for age, gender and BMI of the offspring. The median BMI of the offspring in group A, B and C were 30.0, 28.7 and 31.2 kg/m2, respectively. Heritability estimates of CRP levels ranged from 0.75 to 0.83 and remained significant after excluding for type 2 diabetes mellitus. Our small sample size increases the possibility of a type 1 error.
This is a single report in an adequately powered but limited sample size study identifying the strong heritability of CRP levels. Replication in other large family cohorts is necessary.
These findings support the concept that there is an increased cardiovascular disease risk profile in families of women with PCOS.
This research was supported by National Institutes of Health grants U54HD-034449 and P50 HD044405 (A.D.). Priyathama Vellanki is supported in part by NIH/NIDDK Training Grant T32 DK007169.
PMCID: PMC3571499  PMID: 23257395
C-reactive protein; cardiovascular risk; hyperandrogenism; heritability; first-degree relatives
14.  Effect of an intervention to improve the cardiovascular health of family members of patients with coronary artery disease: a randomized trial 
Family members of patients with coronary artery disease (CAD) have higher risk of vascular events. We conducted a trial to determine if a family heart-health intervention could reduce their risk of CAD.
We assessed coronary risk factors and randomized 426 family members of patients with CAD to a family heart-health intervention (n = 211) or control (n = 215). The intervention included feedback about risk factors, assistance with goal setting and counselling from health educators for 12 months. Reports were sent to the primary care physicians of patients whose lipid levels and blood pressure exceeded threshold values. All participants received printed materials about smoking cessation, healthy eating, weight management and physical activity; the control group received only these materials. The main outcomes (ratio of total cholesterol to high-density lipoprotein [HDL] cholesterol; physical activity; fruit and vegetable consumption) were assessed at 3 and 12 months. We examined group and time effects using mixed models analyses with the baseline values as covariates. The secondary outcomes were plasma lipid levels (total cholesterol, low-density lipoprotein cholesterol, HDL cholesterol and triglycerides); glucose level; blood pressure; smoking status; waist circumference; body mass index; and the use of blood pressure, lipid-lowering and smoking cessation medications.
We found no effect of the intervention on the ratio of total cholesterol to HDL cholesterol. However, participants in the intervention group reported consuming more fruit and vegetables (1.2 servings per day more after 3 mo and 0.8 servings at 12 mo; p < 0.001). There was a significant group by time interaction for physical activity (p = 0.03). At 3 months, those in the intervention group reported 65.8 more minutes of physical activity per week (95% confidence interval [CI] 47.0–84.7 min). At 12 months, participants in the intervention group reported 23.9 more minutes each week (95% CI 3.9–44.0 min).
A health educator–led heart-health intervention did not improve the ratio of total cholesterol to HDL cholesterol but did increase reported physical activity and fruit and vegetable consumption among family members of patients with CAD. Hospitalization of a spouse, sibling or parent is an opportunity to improve cardiovascular health among other family members. Trial registration:, no NCT00552591.
PMCID: PMC3883820  PMID: 24246588
15.  Modest familial risks for multiple sclerosis: a registry-based study of the population of Sweden 
Brain  2014;137(3):770-778.
In a study based on 96% of the roughly 28,000 patients with multiple sclerosis (MS) in Sweden, Westerlind et al. report relative and absolute MS risks for relatives of patients. Risks were lower than most of those previously reported, with an MS sibling risk seven times that of randomly selected controls.
Data on familial recurrence rates of complex diseases such as multiple sclerosis give important hints to aetiological factors such as the importance of genes and environment. By linking national registries, we sought to avoid common limitations of clinic-based studies such as low numbers, poor representation of the population and selection bias. Through the Swedish Multiple Sclerosis Registry and a nationwide hospital registry, a total of 28 396 patients with multiple sclerosis were identified. We used the national Multi-Generation Registry to identify first and second degree relatives as well as cousins, and the Swedish Twin Registry to identify twins of patients with multiple sclerosis. Crude and age corrected familial risks were estimated for cases and found to be in the same range as previously published figures. Matched population-based controls were used to calculate relative risks, revealing lower estimates of familial multiple sclerosis risks than previously reported, with a sibling recurrence risk (λs = 7.1; 95% confidence interval: 6.42–7.86). Surprisingly, despite a well-established lower prevalence of multiple sclerosis amongst males, the relative risks were equal among maternal and paternal relations. A previously reported increased risk in maternal relations could thus not be replicated. An observed higher transmission rate from fathers to sons compared with mothers to sons suggested a higher transmission to offspring from the less prevalent sex; therefore, presence of the so-called ‘Carter effect’ could not be excluded. We estimated the heritability of multiple sclerosis using 74 757 twin pairs with known zygosity, of which 315 were affected with multiple sclerosis, and added information from 2.5 million sibling pairs to increase power. The heritability was estimated to be 0.64 (0.36–0.76), whereas the shared environmental component was estimated to be 0.01 (0.00–0.18). In summary, whereas multiple sclerosis is to a great extent an inherited trait, the familial relative risks may be lower than usually reported.
PMCID: PMC3927700  PMID: 24441172
familial recurrence; multiple sclerosis; familial risk; twin study
16.  Familial Aggregation of Food Allergy and Sensitization to Food Allergens: A Family-Based Study 
The increasing prevalence of food allergy (FA) is a growing clinical and public health problem. The contribution of genetic factors to FA remains largely unknown.
This study examined the pattern of familial aggregation and the degree to which genetic factors contribute to FA and sensitization to food allergens.
This study included 581 nuclear families (2,004 subjects) as part of an ongoing FA study in Chicago, IL, USA. FA was defined by a set of criteria including timing, clinical symptoms obtained via standardized questionnaire interview, and corroborative specific IgE cutoffs for >=95% positive predictive value (PPV) for food allergens measured by Phadia ImmunoCAP. Familial aggregation of FA as well as sensitization to food allergens were examined using generalized estimating equation (GEE) models, with adjustment for important covariates including age, gender, ethnicity and birth order. Heritability was estimated for food-specific IgE measurements.
FA in the index child was a significant and independent predictor of FA in other siblings (OR=2.6, 95%CI:1.2–5.6, p=0.01). There were significant and positive associations among family members (father-offspring, mother-offspring, index-other siblings) for total IgE and specific IgE to all the 9 major food allergens tested in this sample (sesame, peanut, wheat, milk, egg white, soy, walnut, shrimp and cod fish). The estimated heritability of food-specific IgE ranged from 0.15 to 0.35 and was statistically significant for all the 9 tested food allergens.
This family-based study demonstrates strong familial aggregation of food allergy and sensitization to food allergens, especially, among siblings. The heritability estimates indicate that food-specific IgE is likely influenced by both genetic and environmental factors. Together, this study provides strong evidence that both host genetic susceptibilityand environmental factors determine the complex trait of IgE-mediated food allergy.
PMCID: PMC2729087  PMID: 19016802
familial aggregation; heritability; food allergy; sensitization to food allergens; IgE-mediated
17.  Reconsidering the Heritability of Intelligence in Adulthood: Taking Assortative Mating and Cultural Transmission into Account 
Behavior Genetics  2011;42(2):187-198.
Heritability estimates of general intelligence in adulthood generally range from 75 to 85%, with all heritability due to additive genetic influences, while genetic dominance and shared environmental factors are absent, or too small to be detected. These estimates are derived from studies based on the classical twin design and are based on the assumption of random mating. Yet, considerable positive assortative mating has been reported for general intelligence. Unmodeled assortative mating may lead to biased estimates of the relative magnitude of genetic and environmental factors. To investigate the effects of assortative mating on the estimates of the variance components of intelligence, we employed an extended twin-family design. Psychometric IQ data were available for adult monozygotic and dizygotic twins, their siblings, the partners of the twins and siblings, and either the parents or the adult offspring of the twins and siblings (N = 1314). Two underlying processes of assortment were considered: phenotypic assortment and social homogamy. The phenotypic assortment model was slightly preferred over the social homogamy model, suggesting that assortment for intelligence is mostly due to a selection of mates on similarity in intelligence. Under the preferred phenotypic assortment model, the variance of intelligence in adulthood was not only due to non-shared environmental (18%) and additive genetic factors (44%) but also to non-additive genetic factors (27%) and phenotypic assortment (11%).This non-additive nature of genetic influences on intelligence needs to be accommodated in future GWAS studies for intelligence.
Electronic supplementary material
The online version of this article (doi:10.1007/s10519-011-9507-9) contains supplementary material, which is available to authorized users.
PMCID: PMC3276760  PMID: 21969232
Twin-study; Assortative mating; Intelligence; Cognitive ability; Genetic dominance
18.  Genetic and non-genetic correlates of vitamins K and D 
To assess the genetic and nongenetic correlates of circulating measures of vitamins K and D status in a community-based sample of men and women.
A cross-sectional study of 1762 participants of the Framingham Offspring Study (919 women; mean age 59 years). Vitamin K status was measured as plasma phylloquinone and serum percent undercarboxylated osteocalcin (ucOC), and vitamin D was measured using plasma 25-hydroxyvitamin D (25(OH)D). Associations between vitamin K status and vitamin D status with biologically plausible nongenetic factors were assessed using stepwise regression. Heritability and linkage were determined using Sequential Oligogenic Linkage Analysis Routines (SOLAR).
Nongenetic factors accounted for 20.1 and 12.3% of the variability in plasma phylloquinone in men and women respectively, with triglycerides and phylloquinone intake being the primary correlates. In men 12.2% and in women 14.6% of the variability in %ucOC was explained by nongenetic factors in our models. Heritability estimates for these vitamin K status biomarkers were nonsignificant. Season, vitamin D intake, high-density lipoprotein (HDL) cholesterol and waist circumference explained 24.7% (men) and 24.2% (women) of the variability in plasma 25(OH)D. Of the three vitamins examined, only 25(OH)D was significantly heritable (heritability estimate=28.8%, P<0.01), but linkage analysis of 25(OH)D did not achieve genome-wide significance.
Variability in biomarkers of vitamin K status was attributed to nongenetic factors, whereas plasma 25(OH)D was found to be significantly heritable. Further studies are warranted to investigate genetic loci influencing vitamin D status.
PMCID: PMC2681093  PMID: 18030310
vitamin K; phylloquinone; undercarboxylated osteocalcin; vitamin D; heritability; genetics
19.  Parent-Offspring Correlations in Pedometer-Assessed Physical Activity 
PLoS ONE  2011;6(12):e29195.
Physical activity is a major component of a healthy lifestyle in youth and adults. To identify determinants of this complex behavior is an important research objective in the process of designing interventions to promote physical activity at population level. In addition to individual determinants, there is evidence documenting familial influences on physical activity. However, the few studies that have addressed this issue with objective measures did not provide data on parent-offspring physical activity relationships throughout childhood and adolescence. The purpose of this study was to assess familial correlations in pedometer-assessed physical activity.
We measured ambulatory activity in 286 French nuclear families (283 mothers, 237 fathers, and 631 children aged 8–18 years) by pedometer recordings (Yamax Digiwalker DW 450) over a week. Correlations were computed with their 95% confidence intervals (CI) for spouse pairs, siblings, mother-offspring, and father-offspring. Data were expressed as steps per day and computed both for the full recording period and separately for weekdays and weekends.
The correlations were the highest between siblings (r = 0.28, 95%CI: 0.17–0.38). Parent–offspring correlations were significant in mothers (r = 0.21, 95%CI: 0.12–0.30), especially between mothers and daughters (r = 0.24, 95%CI: 0.12–0.36 vs. r = 0.18, 95%CI: 0.05–0.31 for sons), but were almost nonexistent in fathers. Correlations were generally higher on weekend days compared to weekdays. Mother-offspring correlations did not decrease with increasing age of children (r = 0.17, 95%CI: 0.00–0.34 in 8–11-year-olds, r = 0.20, 95%CI: 0.07–0.33 in 12–15-year-olds, and r = 0.25, 95%CI: 0.07–0.39 in ≥16-year-olds). Finally, between-spouse correlations were significant only during weekend days (r = 0.14, 95%CI: 0.01–0.27).
Ambulatory activity correlated within families, with a possible mother effect. Mother-offspring correlations remained significant through the transition from childhood to adolescence. Further studies are required to better understand the respective influences of shared activities, parental modeling and support as well as genetic factors on the familial aggregation of physical activity.
PMCID: PMC3247254  PMID: 22216207
20.  Heritability and major gene effects on left ventricular mass in the Chinese population: a family study 
Genetic components controlling for echocardiographically determined left ventricular (LV) mass are still unclear in the Chinese population.
We conducted a family study from the Chin-San community, Taiwan, and a total of 368 families, 1145 subjects, were recruited to undergo echocardiography to measure LV mass. Commingling analysis, familial correlation, and complex segregation analysis were applied to detect component distributions and the mode of inheritance.
The two-component distribution model was the best-fitting model to describe the distribution of LV mass. The highest familial correlation coefficients were mother-son (0.379, P < .0001) and father-son (0.356, P < .0001). Genetic heritability (h2) of LV mass was estimated as 0.268 ± 0.061 (P < .0001); it decreased to 0.153 ± 0.052 (P = .0009) after systolic blood pressure adjustment. Major gene effects with polygenic components were the best-fitting model to explain the inheritance mode of LV mass. The estimated allele frequency of the gene was 0.089.
There were significant familial correlations, heritability and a major gene effect on LV mass in the population-based families.
PMCID: PMC1579230  PMID: 16945138
21.  Poor school performance in offspring of patients with schizophrenia: What are the mechanisms? 
Psychological medicine  2011;42(1):111-123.
Offspring to patients with schizophrenia exhibit poorer school performance compared to offspring of non-schizophrenic parents. We aimed to elucidate the mechanisms behind this association.
We linked longitudinal national population registers in Sweden and compared school performance among offspring to schizophrenic parents to offspring of non-schizophrenic parents (N=1,439,215 with final grades from compulsory school 1988–2006). To investigate the mechanisms, we studied offspring to schizophrenic patients and controls within the same extended families. We investigated genetic effects by stratifying analyses of parent-child associations according to genetic relatedness (half-cousins, full cousins, and half-siblings). Environmental effects were investigated by comparing school performance of offspring to schizophrenic fathers and to schizophrenic mothers, respectively, and by stratifying the analyses according to environmental relatedness while controlling genetic relatedness (paternal and maternal half-cousins, paternal and maternal half-siblings).
Offspring to parents with schizophrenia had poorer overall school performance than unrelated offspring to non-schizophrenic parents (−0.31 SD). Variability in genetic relatedness greatly moderated the strength of the within-family association (β=−0.23 within exposure-discordant half-cousins, β=−0.13 within exposure-discordant full cousins, and β=0.04 within exposure-discordant half-siblings), while no evidence was found that the environment affected offspring school performance.
Genetic factors account for poorer school performance in children of parents with schizophrenia. This supports that cognitive deficits found in individuals with schizophrenia and their relatives might be genetically inherited. Early detection of prodromal signs and impaired functioning of offspring to patients with schizophrenia could lead to earlier and better tailored interventions.
PMCID: PMC3658106  PMID: 21733288
school performance; offspring; schizophrenia; genetics; environments
22.  Intergenerational Transmission of Childhood Conduct Problems 
Archives of general psychiatry  2007;64(7):820-829.
The familial nature of childhood conduct problems has been well documented, but few genetically informed studies have explicitly explored the processes through which parental conduct problems influence an offspring’s behavior problems.
To delineate the genetic and environmental processes underlying the intergenerational transmission of childhood conduct problems.
We used hierarchical linear models to analyze data from a Children of Twins Study, a quasiexperimental design, to explore the extent to which genetic factors common to both generations, unmeasured environmental factors that are shared by twins, or measured characteristics of both parents confound the intergenerational association.
Participants were recruited from the community and completed a semistructured diagnostic telephone interview.
The research used a high-risk sample of twins, their spouses, and their young adult offspring (n=2554) from 889 twin families in the Australian Twin Registry, but the analyses used sample weights to produce parameter estimates for the community-based volunteer sample of twins.
Main Outcome Measure
Number of conduct disorder symptoms.
The magnitude of the intergenerational transmission was significant for all offspring, though it was stronger for males (effect size [Cohen d]=0.21; 95% confidence interval, 0.15–0.17) than females (d=0.09; 95% confidence interval, 0.05–0.14). The use of the Children of Twins design and measured covariates indicated that the intergenerational transmission of conduct problems for male offspring was largely mediated by environmental variables specifically related to parental conduct disorder (d=0.13; 95% confidence interval, 0.02–0.23). In contrast, the intergenerational transmission of conduct problems was not because of environmentally mediated causal processes for female offspring (d=−0.09; 95% confidence interval, −0.20 to 0.03); a common genetic liability accounted for the intergenerational relations.
The mechanisms underlying the inter-generational transmission of conduct problems depend on the sex of the offspring. The results are consistent with an environmentally mediated causal role of parental conduct problems on behavior problems in males. Common genetic risk, however, confounds the entire inter-generational transmission in female offspring.
PMCID: PMC2965630  PMID: 17606816
23.  Bivariate variance-component analysis, with application to systolic blood pressure and total cholesterol levels in the Framingham Heart Study 
BMC Genetics  2003;4(Suppl 1):S81.
The correlations between systolic blood pressure (SBP) and total cholesterol levels (CHOL) might result from genetic or environmental factors that determine variation in the phenotypes and are shared by family members. Based on 330 nuclear families in the Framingham Heart Study, we used a multivariate normal model, implemented in the software FISHER, to estimate genetic and shared environmental components of variation and genetic and shared environmental correlation between the phenotypes. The natural logarithm of the phenotypes measured at the last visit in both Cohort 1 and 2 was used in the analyses. The antihypertensive treatment effect was corrected before adjustment of the systolic blood pressure for age, sex, and cohort.
The univariate correlation coefficient was statistically significant for sibling pairs and parent-offspring pairs, but not significant for spouse pairs. In the bivariate analysis, the cross-trait correlation coefficients were not statistically significant for all relative pairs. The shared environmental correlation was statistically significant, but the genetic correlation was not significant.
There is no significant evidence for a close genetic correlation between systolic blood pressure and total cholesterol levels. However, some shared environmental factors may determine the variation of both phenotypes.
PMCID: PMC1866521  PMID: 14975149
24.  The Association Between Parental Schizophrenia and Offspring Suicide: A Cousin Comparison approach 
Psychological medicine  2012;43(3):581-590.
This study evaluated the suicide risk among offspring of parents hospitalized for schizophrenia and elucidated the mechanisms behind this association.
We applied a nested case-control design based on a linkage of Swedish population-based registers. Among 12- to 30-year old offspring, we identified 22 850 suicide cases and their parents. For each case-parent pair we matched five healthy controls-parent pairs. All individuals were followed up to the end of 2004. We performed conditional logistic regression models to estimate adjusted odds ratios. To disentangle familial confounding from environmental mechanisms we also compared the population based suicide risk with the observed risk within full-cousins and half-cousins differentially exposed for parental schizophrenia.
Offspring of parents with schizophrenia had a significantly increased risk of suicide after accounting for socioeconomic status, parental suicide and offspring mental illness (odds ratio 1.73 [1.47–2.04]). The suicide risks in offspring of schizophrenic mothers and schizophrenic fathers were similar in magnitude. The suicide risk was also similar across different developmental periods. The offspring of siblings discordant for schizophrenia showed comparable odds ratios within full cousins (odds ratio 2.02 [1.48–2.76]), and within half-cousins (odds ratio 2.03 [0.96–4.28]).
Parental schizophrenia is associated with an increased risk for offspring suicide. The suicide risk in offspring remained unchanged when comparing genetically different relationships, which indicate that parental schizophrenia acts directly through environmental mechanisms. These findings highlight the importance of increased social support to offspring of parents with schizophrenia in order to prevent suicidal events.
PMCID: PMC3669221  PMID: 22703756
25.  Body mass index and height over three generations: evidence from the Lifeways cross-generational cohort study 
BMC Public Health  2012;12:81.
Obesity and its measure of body mass index are strongly determined by parental body size. Debate continues as to whether both parents contribute equally to offspring body mass which is key to understanding the aetiology of the disease. The aim of this study was to use cohort data from three generations of one family to examine the relative maternal and paternal associations with offspring body mass index and how these associations compare with family height to demonstrate evidence of genetic or environmental cross-generational transmission.
669 of 1082 families were followed up in 2007/8 as part of the Lifeways study, a prospective observational cross-generation linkage cohort. Height and weight were measured in 529 Irish children aged 5 to 7 years and were self-reported by parents and grandparents. All adults provided information on self-rated health, education status, and indicators of income, diet and physical activity. Associations between the weight, height, and body mass index of family members were examined with mixed models and heritability estimates computed using linear regression analysis.
Self-rated health was associated with lower BMI for all family members, as was age for children. When these effects were accounted for evidence of familial associations of BMI from one generation to the next was more apparent in the maternal line. Heritability estimates were higher (h2 = 0.40) for mother-offspring pairs compared to father-offspring pairs (h2 = 0.22). In the previous generation, estimates were higher between mothers-parents (h2 = 0.54-0.60) but not between fathers-parents (h2 = -0.04-0.17). Correlations between mother and offspring across two generations remained significant when modelled with fixed variables of socioeconomic status, health, and lifestyle. A similar analysis of height showed strong familial associations from maternal and paternal lines across each generation.
This is the first family cohort study to report an enduring association between mother and offspring BMI over three generations. The evidence of BMI transmission over three generations through the maternal line in an observational study corroborates the findings of animal studies. A more detailed analysis of geno and phenotypic data over three generations is warranted to understand the nature of this maternal-offspring relationship.
PMCID: PMC3359190  PMID: 22276639

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