Richard J. Rose

Genome-wide association study identifies multiple loci influencing human serum metabolite levels

Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 × 10−10) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders.

Breakfast skipping and health-compromising behaviors in adolescents and adults

Objective: To investigate which sociodemographic factors and behaviors are associated with breakfast skipping in adolescents and adults.Design: Five birth cohorts of adolescent twins and their parents received an extensive behavioral and medical self-report questionnaire that also assessed breakfast-eating frequency.Setting: Finland, 1991–1995.Subjects: A population sample of 16-y-old girls and boys (n=5448) and their parents (n=4660).Results: Parental breakfast eating was the statistically most significant factor associated with adolescent breakfast eating. Smoking, infrequent exercise, a low education level at 16, female sex, frequent alcohol use, behavioral disinhibition, and high body mass index (BMI) were significantly associated with adolescent breakfast skipping. In adults, smoking, infrequent exercise, low education level, male sex, higher BMI, and more frequent alcohol use were associated with breakfast skipping. In the adult sample, older individuals had breakfast more often than younger ones. Both adults and adolescents who frequently skipped breakfast were much more likely to exercise very little compared to those who skipped breakfast infrequently. Breakfast skipping was associated with low family socioeconomic status in adults and adolescent boys, but not in girls. Breakfast skipping clustered moderately with smoking, alcohol use, and sedentary lifestyle in both adults and adolescents.Conclusions: Breakfast skipping is associated with health-compromising behaviors in adults and adolescents. Individuals and families who skip breakfast may benefit from preventive efforts that also address risk behaviors other than eating patterns.Sponsorship: National Institute of Alcohol Abuse and Alcoholism (AA08315), Academy of Finland (44069), European Union Fifth Framework Program (QLRT-1999-00916), Yrjö Jahnsson Foundation, and Jalmari and Rauha Ahokas Foundation.

Genetic and environmental factors in health-related behaviors: studies on Finnish twins and twin families

Family, twin and adoption studies have provided evidence for familial and genetic influences on individual differences in disease risk and in human behavior. Attempts to identify individual genes accounting for these differences have not been outstandingly successful to date, and at best, known genes account for only a fraction of the familiality of most traits or diseases. More detailed knowledge of the dynamics of gene action and of specific environmental conditions are needed. Twin and twin-family studies with multiple measurements of risk factors and morbidity over time can permit a much more detailed assessment of the developmental dynamics of disease risk and the unfolding of behavioral risk factors.

A developmental genetic analysis of adult personality: extraversion and neuroticism from 18 to 59 years of age.

Developmental genetic analyses were conducted on Extraversion (E) and Neuroticism (N) scale scores from nearly 15,000 male and female Finnish twins, ages 18-53 at baseline, who were tested on 2 occasions, 6 years apart. Significant genetic effects on both traits were found, at all ages, in men and women, on each measurement occasion. For E, heritability was invariant across sex but decreased from late adolescence to the late 20s, with a smaller additional decrease at about 50 years of age. Heritability for N also decreased from late adolescence to late 20s and remained stable thereafter. For all ages after the early 20s, heritability of N was significantly higher among women. Means for E and N were sex-dependent and, apparently, influenced by cohort and time of assessment, as well as by age. There was little evidence of new genetic contributions to individual differences after age 30; in contrast, significant new environmental effects emerged at every age.

Hostility as a risk factor for mortality and ischemic heart disease in men.

&NA; We report the association between hostility and the incidence of ischemic heart disease (IHD) in 3,750 Finnish men aged 40–59. Hostility was assessed from self‐ratings on irritability, ease of anger‐arousal, and argumentativeness, and four groups were formed from the summed hostility ratings. At baseline, the age‐adjusted relative risk (RR) of the prevalence of angina pectoris between the highest and lowest hostility groups was 2.88 (95% confidence limits (CL), range 1.71–4.77). A three‐year follow‐up yielded 65 deaths and 109 IHD‐incident cases. Hostility did not predict IHD among healthy men, but among men with previous IHD and hypertension (N = 104), the age‐adjusted RR of IHD between the highest and lowest hostility groups was 12.9 (95% CL, 3.92–42.6). After standardization for smoking, obesity, heavy alcohol use, and snoring, the RR was 14.6 (95% CL, 1.94–110). When the degree of dyspnea at baseline was also standardized, the RR was 21.1 (95% CL, 1.59–282). Our data suggest that extreme hostility is not a consequence of symptom severity; rather, hostility is a strong determinant of coronary attack among hypertensive men with IHD.

Physical Inactivity and Obesity: A Vicious Circle

Objective: Physical activity (PA) begins to decline in adolescence with a concomitant increase in weight. We hypothesized that a vicious circle may arise between decreasing PA and weight gain from adolescence to early adulthood.

Pubertal Timing and Substance Use: Associations between and within Families across Late Adolescence.

In the present study, between-family analyses of data from adolescent twin girls offer new evidence that early menarche is associated with earlier initiation and greater frequency of smoking and drinking. The role of personality factors and peer relationships in that association was investigated, and little support was found for their involvement. Novel within-family analyses replicating associations of substance use with pubertal timing in contrasts of twin sisters selected for extreme discordance for age at menarche are reported. Within-family replications demonstrated that the association of pubertal timing with substance use cannot be explained solely by between-family confounds. Within-family analyses demonstrated contextual modulation of the influence of pubertal timing: Its impact on drinking frequency is apparent only among girls in urban settings. Sibling comparisons illustrate a promising analytic tool for studying diverse developmental outcomes.

Parental Monitoring Moderates the Importance of Genetic and Environmental Influences on Adolescent Smoking

Although there is a substantial literature on the role of parenting in adolescent substance use, most parenting effects have been small in magnitude and studied outside the context of genetically informative designs, raising debate and controversy about the influence that parents have on their children (D. C. Rowe, 1994). Using a genetically informative twin-family design, the authors studied the role of parental monitoring on adolescent smoking at age 14. Although monitoring had only small main effects, consistent with the literature, there were dramatic moderation effects associated with parental monitoring: At high levels of parental monitoring, environmental influences were predominant in the etiology of adolescent smoking, but at low levels of parental monitoring, genetic influences assumed far greater importance. These analyses demonstrate that the etiology of adolescent smoking varies dramatically as a function of parenting.

Distribution and heritability of BMI in Finnish adolescents aged 16y and 17y: a study of 4884 twins and 2509 singletons.

OBJECTIVE:1) To estimate the heritability of body mass index (BMI) in twins aged 16 y and 17 y, with a special emphasis on gender-specific genetic effects and 2) to compare heights, weights, BMIs, and prevalences of ‘overweight’ (BMI≥≥25 kg/m2) in these twins and in singletons aged 16.5 y.DESIGN:Cross-sectional and longitudinal epidemiological questionnaire study of twins at ages 16 y and 17 y, and cross-sectional study of singletons at age 16.5 y.MEASUREMENTS:BMI (kg/m2) was calculated from self-reported heights (m) and weights (kg).SUBJECTS:4884 twins (2299 boys, 2585 girls) at baseline (age 16 y), 4401 twins (2002 boys, 2399 girls) at age 17 y, and 2509 singletons (1147 boys, 1362 girls) at age 16.5 y. Both twin and singleton samples are nationally representative.RESULTS:At the ages of 16 y and 17 y, genetic effects accounted for over 80% of the interindividual variation of BMI. The correlations for male–female pairs were smaller than for either male-male or female–female dizygotic pairs. The singletons, especially the boys, had a higher BMI than the twins. Nine percent of singleton boys, but only 4–6% of twin boys and twin and singleton girls were ‘overweight’ (BMI≥≥25 kg/m2).CONCLUSIONS:Among adolescents, genetic factors play a significant role in the causes of variation in BMI. The genetic modelling suggested that the sets of genes explaining the variation of BMI may differ in males and females. At this age, the twin boys, but not girls, seem to be leaner than singletons. Further follow-up will indicate whether these small differences disappear, and if not, what implications it might have to the generalizability of twin studies.

Self-reported hostility and suicidal acts, accidents, and accidental deaths: a prospective study of 21,443 adults aged 25 to 59.

&NA; The association of self‐reported hostility with morbidity and mortality due to external causes, including suicidal acts, was analyzed in 10,586 Finnish men and 10,857 Finnish women aged 24 to 59 years. Hostility was assessed from self‐ratings on irritability, ease of anger‐arousal, and argumentativeness. Three groups, low (33.6% of subjects), intermediate (50.6%), and extreme (15.9%), were formed from the self‐reported hostility scores. A 6‐year mortality follow‐up yielded 76 violent deaths among men and 11 among women. A 4‐year morbidity follow‐up found 399 hospitalizations due to external causes among men and 169 among women. Among men, the risk ratio between the highest and lowest hostility groups was 1.51 (95% confidence interval, 1.16–1.96) for all events due to external causes and 3.6 (95% confidence interval, 1.63–7.89) for suicidal behavior, when effects of age, marital status, social status, and self‐reported alcohol use were controlled in a multivariate model. No association was observed between traffic‐related injuries and hostility. Hostility did not predict accidents or accidental deaths or suicidal behavior among women.