Per Tynelius

Paternal age and schizophrenia: a population based cohort study

Abstract Objective To investigate the association of paternal age at conception with the risk of offspring developing schizophrenia. Design A population based cohort study. Setting Sweden. Subjects 754 330 people born in Sweden between 1973 and 1980 and still alive and resident in Sweden at age 16 years. Main outcome measures Hospital admission with schizophrenia or non-schizophrenic, non-affective psychosis. Results After adjustment for birth related exposures, socioeconomic factors, family history of psychosis, and early parental death the overall hazard ratio for each 10 year increase in paternal age was 1.47 (95% confidence interval 1.23 to 1.76) for schizophrenia and 1.12 (0.98 to 1.29) for non-schizophrenic non-affective psychosis. This association between paternal age and schizophrenia was present in those with no family history of the disorder (hazard ratio for each 10 year increase in paternal age 1.60, 1.32 to 1.92), but not in those with a family history (0.91, 0.44 to 1.89) (P = 0.04 for interaction). Conclusions Advancing paternal age is an important independent risk factor for schizophrenia. The stronger association between paternal age and schizophrenia in people without a family history provides further evidence that accumulation of de novo mutations in paternal sperm contributes to the overall risk of schizophrenia.

Childhood Socioeconomic Position and Objectively Measured Physical Capability Levels in Adulthood: A Systematic Review and Meta-Analysis

Background Grip strength, walking speed, chair rising and standing balance time are objective measures of physical capability that characterise current health and predict survival in older populations. Socioeconomic position (SEP) in childhood may influence the peak level of physical capability achieved in early adulthood, thereby affecting levels in later adulthood. We have undertaken a systematic review with meta-analyses to test the hypothesis that adverse childhood SEP is associated with lower levels of objectively measured physical capability in adulthood. Methods and Findings Relevant studies published by May 2010 were identified through literature searches using EMBASE and MEDLINE. Unpublished results were obtained from study investigators. Results were provided by all study investigators in a standard format and pooled using random-effects meta-analyses. 19 studies were included in the review. Total sample sizes in meta-analyses ranged from N = 17,215 for chair rise time to N = 1,061,855 for grip strength. Although heterogeneity was detected, there was consistent evidence in age adjusted models that lower childhood SEP was associated with modest reductions in physical capability levels in adulthood: comparing the lowest with the highest childhood SEP there was a reduction in grip strength of 0.13 standard deviations (95% CI: 0.06, 0.21), a reduction in mean walking speed of 0.07 m/s (0.05, 0.10), an increase in mean chair rise time of 6% (4%, 8%) and an odds ratio of an inability to balance for 5s of 1.26 (1.02, 1.55). Adjustment for the potential mediating factors, adult SEP and body size attenuated associations greatly. However, despite this attenuation, for walking speed and chair rise time, there was still evidence of moderate associations. Conclusions Policies targeting socioeconomic inequalities in childhood may have additional benefits in promoting the maintenance of independence in later life.

Muscular strength in male adolescents and premature death: cohort study of one million participants

Objectives To explore the extent to which muscular strength in adolescence is associated with all cause and cause specific premature mortality (<55 years). Design Prospective cohort study. Setting Sweden. Participants 1 142 599 Swedish male adolescents aged 16-19 years were followed over a period of 24 years. Main outcome measures Baseline examinations included knee extension, handgrip, and elbow flexion strength tests, as well as measures of diastolic and systolic blood pressure and body mass index. Cox regression was used to estimate hazard ratios for mortality according to muscular strength categories (tenths). Results During a median follow-up period of 24 years, 26 145 participants died. Suicide was a more frequent cause of death in young adulthood (22.3%) than was cardiovascular diseases (7.8%) or cancer (14.9%). High muscular strength in adolescence, as assessed by knee extension and handgrip tests, was associated with a 20-35% lower risk of premature mortality due to any cause or cardiovascular disease, independently of body mass index or blood pressure; no association was observed with mortality due to cancer. Stronger adolescents had a 20-30% lower risk of death from suicide and were 15-65% less likely to have any psychiatric diagnosis (such as schizophrenia and mood disorders). Adolescents in the lowest tenth of muscular strength showed by far the highest risk of mortality for different causes. All cause mortality rates (per 100 000 person years) ranged between 122.3 and 86.9 for the weakest and strongest adolescents; corresponding figures were 9.5 and 5.6 for mortality due to cardiovascular diseases and 24.6 and 16.9 for mortality due to suicide. Conclusions Low muscular strength in adolescents is an emerging risk factor for major causes of death in young adulthood, such as suicide and cardiovascular diseases. The effect size observed for all cause mortality was equivalent to that for well established risk factors such as elevated body mass index or blood pressure.

Heritability of body size and muscle strength in young adulthood: a study of one million Swedish men

Moderate heritability for skeletal muscle strength has been reported in twin studies, but genetic co‐variation between muscle strength at different parts of body and body size is not well known. Further, representativeness of twin cohorts needs to be critically evaluated. Height, weight, elbow flexion, hand grip and knee extension strength were measured in young adulthood in 1,139,963 Swedish men born between 1951 and 1976. We identified 154,970 full‐brother pairs and 1582 monozygotic (MZ) and 1864 same‐sex dizygotic (DZ) complete twin pairs. The data were analyzed using quantitative genetic modeling for twin and family data. Twins compared to singletons and MZ twins compared to DZ twins were shorter, lighter and had lower muscle strength. In singletons, there was more variation in weight and the strength measures compared to twins with known zygosity but not when compared to twins with unknown zygosity. Full‐sib correlations for these traits were lower than DZ correlations. Additive genetic factors explained 81% of variation in height, 59% in body mass index and 50–60% in the strength measures. Additive genetic correlations varied from 0.13 between height and elbow flexion strength to 0.78 between elbow flexion and hand grip strength. Our results suggest that extra variation may exist in general populations not found in twin samples, probably because of selection due to non‐participation. This may have inflated heritability estimates in previous twin studies. Nonetheless, we showed that genetic factors affect muscle strength and part of these genes are common to different strength indicators and body size. Genet. Epidemiol.

Association of blood pressure in late adolescence with subsequent mortality: cohort study of Swedish male conscripts

Objective To investigate the nature and magnitude of relations of systolic and diastolic blood pressures in late adolescence to mortality. Design Nationwide cohort study. Setting General community in Sweden. Participants Swedish men (n=1 207 141) who had military conscription examinations between 1969 and 1995 at a mean age of 18.4 years, followed up for a median of 24 (range 0-37) years. Main outcome measures Total mortality, cardiovascular mortality, and non-cardiovascular mortality. Results During follow-up, 28 934 (2.4%) men died. The relation of systolic blood pressure to total mortality was U shaped, with the lowest risk at a systolic blood pressure of about 130 mm Hg. This pattern was driven by the relation to non-cardiovascular mortality, whereas the relation to cardiovascular mortality was monotonically increasing (higher risk with higher blood pressure). The relation of diastolic blood pressure to mortality risk was monotonically increasing and stronger than that of systolic blood pressure, in terms of both relative risk and population attributable fraction (deaths that could be avoided if blood pressure was in the optimal range). Relations to cardiovascular and non-cardiovascular mortality were similar, with an apparent risk threshold at a diastolic blood pressure of about 90 mm Hg, below which diastolic blood pressure and mortality were unrelated, and above which risk increased steeply with higher diastolic blood pressures. Conclusions In adolescent men, the relation of diastolic blood pressure to mortality was more consistent than that of systolic blood pressure. Considering current efforts for earlier detection and prevention of risk, these observations emphasise the risk associated with high diastolic blood pressure in young adulthood.

Association of body size and muscle strength with incidence of coronary heart disease and cerebrovascular diseases: a population-based cohort study of one million Swedish men

BACKGROUND Muscle strength and body size may be associated with coronary heart disease (CHD) and stroke risk. However, perhaps because of a low number of cases, existing evidence is inconsistent. METHODS Height, weight, systolic (SBP) and diastolic blood pressure (DBP), elbow flexion, hand grip and knee extension strength were measured in young adulthood in 1 145 467 Swedish men born between 1951 and 1976. Information on own and parental social position was derived from censuses. During the register-based follow-up until the end of 2006, 12 323 CHD and 8865 stroke cases emerged, including 1431 intracerebral haemorrhage, 1316 subarachoid haemorrhage and 2944 intracerebral infarction cases. Hazard ratios (HR) per 1 SD in the exposures of interest were computed using Cox proportional hazard model. RESULTS Body mass index (BMI, kg/m(2)) showed increased risk with CHD and intracerebral infarction, whereas for intracerebral and subarachoid haemorrhage both under- and overweight was associated with increased risk. Height was inversely associated with CHD and all types of stroke. After adjustment for height, BMI, SBP, DBP and social position, all strength indicators were inversely associated with disease risk. For CHD and intracerebral infarction, grip strength showed the strongest association (HR = 0.89 and 0.91, respectively) whereas for intracerebral and subarachoid haemorrhage, knee extension strength was the best predictor (HR = 0.88 and 0.92, respectively). CONCLUSION Body size and muscle strength in young adulthood are important predictors of risk of CHD and stroke in later life. In addition to adiposity, underweight needs attention since it may predispose to cerebrovascular complications.

IQ in Early Adulthood and Mortality By Middle Age Cohort Study of 1 Million Swedish Men

Background: High premorbid IQ test scores are related to a reduced rate of later total mortality, although little is known about the shape of this association (ie, dose-response versus threshold), or the role of mediating and confounding factors in explaining it. Additionally, the link between IQ and cause-specific mortality has been little explored. Methods: A cohort of over 1 million Swedish men who underwent IQ testing at military service conscription at about 18 years of age was followed for mortality experience until middle age. Results: An average of 20 years of follow-up gave rise to 14,498 deaths in an analytical sample of 994,262. In basic analyses adjusting for age, year of birth, and conscription testing center, lower IQ scores were associated with an elevated risk of all-cause mortality (HRper 1-SD decrease in IQ; 1.32; 95% confidence interval = 1.30–1.34). This relation was incremental across the full IQ range, and was robust to adjustment for indicators of childhood social circumstances. The association did not appear to be mediated by factors measured concurrent with IQ (blood pressure, body mass index, or cigarette smoking), nor was it attributable to reverse causality. However, controlling for education (a close correlate of IQ) led to marked attenuation. IQ was also associated with mortality from accidents, coronary heart disease, and suicides, but not cancer. Conclusions: In this large cohort we found a robust stepwise relation between early adult IQ and risk of total and accident mortality in men.

Intelligence in early adulthood and subsequent hospitalization for mental disorders

Background: Lower intelligence is a risk factor for several specific mental disorders. It is unclear whether it is a risk factor for all mental disorders, and whether it might be associated with illness severity. We examined the relation of premorbid intelligence with risk of hospital admission and with total admission rates, for the whole range of mental disorders. Methods: Participants were 1,049,663 Swedish men who took tests of intelligence on conscription into military service and were followed up with regard to hospital admissions for mental disorder, for a mean of 22.6 years. International Classification of Diseases diagnoses were recorded at discharge from the hospital. Results: Risk of hospital admission for all categories of mental disorder rose with each point decrease in the 9-point IQ score. For a standard deviation decrease in IQ, age-adjusted hazard ratios (95% confidence interval) were 1.60 for schizophrenia (1.55–1.65), 1.49 for other nonaffective psychoses (1.45–1.53), 1.50 for mood disorders (1.47–1.51), 1.51 for neurotic disorders (1.48–1.54), 1.60 for adjustment disorders (1.56–1.64), 1.75 for personality disorders (1.70–1.80), 1.75 for alcohol-related (1.73–1.77), and 1.85 for other substance-use disorders (1.82–1.88). Lower intelligence was also associated with greater comorbidity. Associations changed little on adjustment for potential confounders. Men with lower intelligence had higher total admission rates for mental disorders, a possible marker of clinical severity. Conclusions: Lower intelligence is a risk factor for the whole range of mental disorders and for illness severity.

The association between BMI and mortality using offspring BMI as an indicator of own BMI: large intergenerational mortality study

Objectives To obtain valid estimates of the association between body mass index (BMI) and mortality by using offspring BMI as an instrumental variable for own BMI. Design Cohort study based on record linkage, with 50 years of follow-up for mortality. Associations of offspring BMI with all cause and cause specific maternal and paternal mortality were estimated as hazard ratios per standard deviation of offspring BMI. Setting A large intergenerational prospective population based database covering the general population of Sweden. Participants More than one million Swedish parent-son pairs. Results The final dataset analysed contained information on 1 018 012 mother-son pairs (122 677 maternal deaths) and 1 004 617 father-son pairs (242 126 paternal deaths). For some causes of death, the patterns of associations between offspring BMI and mortality were similar to those seen for own BMI and mortality in previous studies. Parental mortality from diabetes, coronary heart disease, and kidney cancer had the strongest positive associations with offspring BMI (for example, hazard ratio (HR) for coronary heart disease per standard deviation increase in offspring BMI for mothers 1.15, 95% CI 1.14 to 1.17 and for fathers 1.10, 1.09 to 1.11). However, in contrast to the inverse association of own BMI with lung cancer and respiratory disease mortality seen in other studies, there was a positive association between offspring BMI and lung cancer mortality in mothers (1.12, 1.09 to 1.15) and fathers (1.03, 1.02 to 1.05) and between offspring BMI and respiratory mortality in mothers (1.05, 1.02 to 1.08) and fathers (1.02, 1.00 to 1.04). Associations of own BMI and offspring BMI with all cause, cardiovascular disease related, and non-cardiovascular disease related mortality were compared in a subset of father-son pairs (n=72 815). When offspring BMI was used as an instrumental variable for paternal BMI, the causal association between BMI and paternal cardiovascular disease mortality (HR per standard deviation of BMI 1.82, 95% CI 1.17 to 2.83) was stronger than that indicated by the directly observed association between own BMI and cardiovascular disease mortality (1.45, 1.31 to 1.61). Conclusions Use of offspring BMI as a predictor of own BMI, a technique that avoids problems of reverse causality, suggests that positive associations of BMI with all cause and cardiovascular mortality may be underestimated in conventional observational studies. Use of offspring BMI instead of own BMI in analyses of respiratory disease and lung cancer mortality, for which previous studies have reported consistent and strong inverse associations with own BMI, suggests that such studies have overstated the apparent adverse consequences of lower BMI with respect to these outcomes.

Genetics of Pubertal Timing and Its Associations With Relative Weight in Childhood and Adult Height: The Swedish Young Male Twins Study

OBJECTIVE. Previous studies have suggested that the timing of puberty is associated with BMI in childhood and adult stature. Because the genetic background of these associations is not thoroughly investigated, we aimed to analyze it in a longitudinal twin cohort. METHODS. We studied a Swedish cohort of 99 monozygotic and 76 dizygotic twin pairs born between 1973 and 1979 with weight and length or height measured annually from birth to age 18 years. Age at onset of pubertal growth spurt, age at peak height velocity, and final height were estimated by a parametric JPA2 growth model. The genetic architecture and mutual associations of these traits and childhood BMI were analyzed by linear structural equation modeling. RESULTS. The heritability estimate was 0.91 for age at onset of pubertal growth spurt, 0.93 for age at peak height velocity, and 0.97 for adult height. Age at onset of pubertal growth spurt was negatively associated with BMI from 1 to 10 years of age and stature in early adulthood. For age at peak height velocity, we found similar associations with childhood BMI and stature in early adulthood. These associations were explained by common genetic factors. CONCLUSION. Growth during puberty is strictly genetically regulated. These genetic factors also explain why boys who matured early had higher BMI through childhood and taller stature in early adulthood.