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Background: Violent criminality is at least moderately heritable, but the mechanisms behind this remain largely unexplained. Height, a highly heritable trait, may be involved but no study has estimated the effect of height on crime while simultaneously accounting for important demographic, biological and other heritable confounders., Methods: We linked nationwide, longitudinal registers for 760 000 men who underwent mandatory military conscription from 1980 through 1992 in Sweden, to assess the association between height and being convicted of a violent crime. We used Cox proportional hazard modelling and controlled for three types of potential confounders: physical characteristics, childhood demographics and general cognitive ability (intelligence)., Results: In unadjusted analyses, height had a moderate negative relationship to violent crime; the shortest of men were twice as likely to be convicted of a violent crime as the tallest. However, when simultaneously controlling for all measured confounders, height was weakly and positively related to violent crime. Intelligence had the individually strongest mitigating effect on the height-crime relationship., Conclusions: Although shorter stature was associated with increased risk of violent offending, our analyses strongly suggested that this relationship was explained by intelligence and other confounding factors. Hence, it is unlikely that height, a highly heritable physical characteristic, accounts for much of the unexplained heritability of violent criminality., (© The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Importance: Autism spectrum disorder (ASD) aggregates in families, but the individual risk and to what extent this is caused by genetic factors or shared or nonshared environmental factors remains unresolved., Objective: To provide estimates of familial aggregation and heritability of ASD., Design, Setting, and Participants: A population-based cohort including 2,049,973 Swedish children born 1982 through 2006. We identified 37,570 twin pairs, 2,642,064 full sibling pairs, 432,281 maternal and 445,531 paternal half sibling pairs, and 5,799,875 cousin pairs. Diagnoses of ASD to December 31, 2009 were ascertained., Main Outcomes and Measures: The relative recurrence risk (RRR) measures familial aggregation of disease. The RRR is the relative risk of autism in a participant with a sibling or cousin who has the diagnosis (exposed) compared with the risk in a participant with no diagnosed family member (unexposed). We calculated RRR for both ASD and autistic disorder adjusting for age, birth year, sex, parental psychiatric history, and parental age. We estimated how much of the probability of developing ASD can be related to genetic (additive and dominant) and environmental (shared and nonshared) factors., Results: In the sample, 14,516 children were diagnosed with ASD, of whom 5689 had autistic disorder. The RRR and rate per 100,000 person-years for ASD among monozygotic twins was estimated to be 153.0 (95% CI, 56.7-412.8; rate, 6274 for exposed vs 27 for unexposed ); for dizygotic twins, 8.2 (95% CI, 3.7-18.1; rate, 805 for exposed vs 55 for unexposed); for full siblings, 10.3 (95% CI, 9.4-11.3; rate, 829 for exposed vs 49 for unexposed); for maternal half siblings, 3.3 (95% CI, 2.6-4.2; rate, 492 for exposed vs 94 for unexposed); for paternal half siblings, 2.9 (95% CI, 2.2-3.7; rate, 371 for exposed vs 85 for unexposed); and for cousins, 2.0 (95% CI, 1.8-2.2; rate, 155 for exposed vs 49 for unexposed). The RRR pattern was similar for autistic disorder but of slightly higher magnitude.We found support for a disease etiology including only additive genetic and nonshared environmental effects. The ASD heritability was estimated to be 0.50 (95% CI, 0.45-0.56) and the autistic disorder heritability was estimated to 0.54 (95% CI, 0.44-0.64)., Conclusions and Relevance: Among children born in Sweden, the individual risk of ASD and autistic disorder increased with increasing genetic relatedness. Heritability of ASD and autistic disorder were estimated to be approximately 50%. These findings may inform the counseling of families with affected children.

Importance: Advancing paternal age is associated with increased genetic mutations during spermatogenesis, which research suggests may cause psychiatric morbidity in the offspring. The effects of advancing paternal age at childbearing on offspring morbidity remain unclear, however, because of inconsistent epidemiologic findings and the inability of previous studies to rigorously rule out confounding factors., Objective: To examine the associations between advancing paternal age at childbearing and numerous indexes of offspring morbidity., Design, Setting, and Participants: We performed a population-based cohort study of all individuals born in Sweden in 1973-2001 (N = 2,615,081), with subsets of the data used to predict childhood or adolescent morbidity. We estimated the risk of psychiatric and academic morbidity associated with advancing paternal age using several quasi-experimental designs, including the comparison of differentially exposed siblings, cousins, and first-born cousins., Exposure: Paternal age at childbearing., Main Outcomes and Measures: Psychiatric (autism, attention-deficit/hyperactivity disorder, psychosis, bipolar disorder, suicide attempt, and substance use problem) and academic (failing grades and low educational attainment) morbidity., Results: In the study population, advancing paternal age was associated with increased risk of some psychiatric disorders (eg, autism, psychosis, and bipolar disorders) but decreased risk of the other indexes of morbidity. In contrast, the sibling-comparison analyses indicated that advancing paternal age had a dose-response relationship with every index of morbidity, with the magnitude of the associations being as large or larger than the estimates in the entire population. Compared with offspring born to fathers 20 to 24 years old, offspring of fathers 45 years and older were at heightened risk of autism (hazard ratio [HR] = 3.45; 95% CI, 1.62-7.33), attention-deficit/hyperactivity disorder (HR = 13.13; 95% CI, 6.85-25.16), psychosis (HR = 2.07; 95% CI, 1.35-3.20), bipolar disorder (HR = 24.70; 95% CI, 12.12-50.31), suicide attempts (HR = 2.72; 95% CI, 2.08-3.56), substance use problems (HR = 2.44; 95% CI, 1.98-2.99), failing a grade (odds ratio [OR] = 1.59; 95% CI, 1.37-1.85), and low educational attainment (OR = 1.70; 95% CI, 1.50-1.93) in within-sibling comparisons. Additional analyses using several quasi-experimental designs obtained commensurate results, further strengthening the internal and external validity of the findings., Conclusions and Relevance: Advancing paternal age is associated with increased risk of psychiatric and academic morbidity, with the magnitude of the risks being as large or larger than previous estimates. These findings are consistent with the hypothesis that new genetic mutations that occur during spermatogenesis are causally related to offspring morbidity.

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.

Reproductive success is widely used as a measure of fitness. However, offspring quantity may not reflect the genetic contribution to subsequent generations if there is nonrandom variation in offspring quality. Offspring quality is likely to be an important component of human fitness, and tradeoffs between offspring quantity and quality have been reported. As such, studies using offspring quantity as a proxy for fitness may yield erroneous projections of evolutionary change, for example if there is little or no genetic variance in number of grandoffspring or if its genetic variance is to some extent independent of the genetic variance in number of offspring. To address this, we performed a quantitative genetic analysis on the reproductive history of 16,268 Swedish twins born between 1915 and 1929 and their offspring. There was significant sex limitation in the sources of familial variation, but the magnitudes of the genetic and environmental effects were the same in males and females. We found significant genetic variation in number of offspring and grandoffspring (heritability = 24% and 16%, respectively), and genetic variation in the two variables completely overlapped--i.e., there was a perfect genetic correlation between number of offspring and grandoffspring. Shared environment played a smaller but significant role in number of offspring and grandoffspring; again, there was a perfect shared environmental correlation between the two variables. These findings support the use of lifetime reproductive success as a proxy for fitness in populations like the one used here, but we caution against generalizing this conclusion to other kinds of human societies.

Twins, full siblings, and half-siblings are increasingly used as comparison groups in matched cohort and matched case-control studies. The "within-pair" estimates acquired through these comparisons are free from confounding from all factors that are shared by the siblings. This has made sibling comparisons popular in studying associations thought likely to suffer confounding from socioeconomic or genetic factors. Despite the wide application of these designs in epidemiology, they have received little scrutiny from a statistical or methodological standpoint. In this paper we show, analytically and through a series of simulations, that the standard interpretation of the models is subject to several limitations that are rarely acknowledged.Although within-pair estimates will not be confounded by factors shared by the siblings, such estimates are more severely biased by non-shared confounders than the unpaired estimate. If siblings are less similar with regard to confounders than to the exposure under study, the within-pair estimate will always be more biased than the ordinary unpaired estimate. Attenuation of associations due to random measurement error in exposure will also be higher in the within-pair estimate, leading within-pair associations to be weaker than corresponding unpaired associations, even in the absence of confounding. Implications for the interpretation of sibling comparison results are discussed.

Children born to older fathers are at higher risk to develop severe psychopathology (e.g., schizophrenia and bipolar disorder), possibly because of increased de novo mutations during spermatogenesis with older paternal age. Because severe psychopathology is correlated with antisocial behavior, we examined possible associations between advancing paternal age and offspring violent offending. Interlinked Swedish national registers provided information on fathers' age at childbirth and violent criminal convictions in all offspring born from 1958 to 1979 (N = 2,359,921). We used ever committing a violent crime and number of violent crimes as indices of violent offending. The data included information on multiple levels; we compared differentially exposed siblings in within-family analyses to rigorously test causal influences. In the entire population, advancing paternal age predicted offspring violent crime according to both indices. Congruent with a causal effect, this association remained for rates of violent crime in within-family analyses. However, in within-family analyses, we found no association with ever committing a violent crime, suggesting that factors shared by siblings (genes and environment) confounded this association. Life-course persistent criminality has been proposed to have a partly biological etiology; our results agree with a stronger biological effect (i.e., de novo mutations) on persistent violent offending.

Background: Offspring of patients with schizophrenia exhibit poorer school performance compared with offspring of non-schizophrenic parents. We aimed to elucidate the mechanisms behind this association., Method: We linked longitudinal national population registers in Sweden and compared school performance among offspring of schizophrenic parents with offspring of non-schizophrenic parents (1 439 215 individuals with final grades from compulsory school 1988-2006). To investigate the mechanisms, we studied offspring of 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 of schizophrenic fathers and of 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)., Results: Offspring of parents with schizophrenia had poorer overall school performance than unrelated offspring of non-schizophrenic parents (-0.31 s.d.). 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, β=0.04 within exposure-discordant half-siblings), while no evidence was found that the environment affected offspring school performance., Conclusions: 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 of patients with schizophrenia could lead to earlier and better tailored interventions.

Background: In utero exposure to tobacco smoking has been suggested to cause persistent alterations in cognitive functioning. We examined if mothers' smoking during pregnancy (SDP) is associated with long-term impairment in offspring stress coping and the causal mechanism behind a possible link., Methods: We used a large cohort (n = 187,106) of young males in Sweden (mean age = 18.2 years), who underwent a semi-structured psychological assessment in 1997-2006, including an evaluation of stress coping ability, as part of the compulsory military conscript examination. We compared differentially exposed siblings within nuclear families and cousins in extended families and used multilevel structural equation models to disentangle genetic from environmental contributions to the association between SDP and stress coping., Results: SDP and offspring stress coping was moderately strongly associated when comparing unrelated individuals [regression coefficient (b) = -0.38 on a nine-point scale; 95% confidence interval (CI) -0.40 to -0.36, P < 0.0001]. In contrast, it disappeared when siblings were compared (b = 0.11; 95% CI -0.01 to 0.23, P = 0.071). This familial confounding was entirely due to genetic influences., Conclusions: SDP is an established risk factor for pregnancy- and birth-related complications. However, we found no long-term effect of SDP on offspring stress coping. Rather, the observed association was due to familial confounding of genetic origin; women prone to SDP also transmit genes to their children that are associated with poorer coping with stress.