Anna C. Svensson

Fecundity of Patients With Schizophrenia, Autism, Bipolar Disorder, Depression, Anorexia Nervosa, or Substance Abuse vs Their Unaffected Siblings

CONTEXT It is unknown how genetic variants conferring liability to psychiatric disorders survive in the population despite strong negative selection. However, this is key to understanding their etiology and designing studies to identify risk variants. OBJECTIVES To examine the reproductive fitness of patients with schizophrenia and other psychiatric disorders vs their unaffected siblings and to evaluate the level of selection on causal genetic variants. DESIGN We measured the fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse and their unaffected siblings compared with the general population. SETTING Population databases in Sweden, including the Multi-Generation Register and the Swedish Hospital Discharge Register. PARTICIPANTS In total, 2.3 million individuals among the 1950 to 1970 birth cohort in Sweden. MAIN OUTCOME MEASURES Fertility ratio (FR), reflecting the mean number of children compared with that of the general population, accounting for age, sex, family size, and affected status. RESULTS Except for women with depression, affected patients had significantly fewer children (FR range for those with psychiatric disorder, 0.23-0.93; P < 10-10). This reduction was consistently greater among men than women, suggesting that male fitness was particularly sensitive. Although sisters of patients with schizophrenia and bipolar disorder had increased fecundity (FR range, 1.02-1.03; P < .01), this was too small on its own to counterbalance the reduced fitness of affected patients. Brothers of patients with schizophrenia and autism showed reduced fecundity (FR range, 0.94-0.97; P < .001). Siblings of patients with depression and substance abuse had significantly increased fecundity (FR range, 1.01-1.05; P < 10-10). In the case of depression, this more than compensated for the lower fecundity of affected individuals. CONCLUSIONS Our results suggest that strong selection exists against schizophrenia, autism, and anorexia nervosa and that these variants may be maintained by new mutations or an as-yet unknown mechanism. Bipolar disorder did not seem to be under strong negative selection. Vulnerability to depression, and perhaps substance abuse, may be preserved by balancing selection, suggesting the involvement of common genetic variants in ways that depend on other genes and on environment.

Parental socioeconomic status and risk of offspring autism spectrum disorders in a Swedish population-based study.

OBJECTIVE Epidemiological studies in the United States consistently find autism spectrum disorders (ASD) to be overrepresented in high socioeconomic status (SES) families. These findings starkly contrast with SES gradients of many health conditions, and may result from SES inequalities in access to services. We hypothesized that prenatal measures of low, not high, parental SES would be associated with an increased risk of offspring ASD, once biases in case ascertainment are minimized. METHOD We tested this hypothesis in a population-based study in Sweden, a country that has free universal healthcare, routine screening for developmental problems, and thorough protocols for diagnoses of ASD. In a case-control study nested in a total population cohort of children aged 0 to 17 years living in Stockholm County between 2001 and 2007 (N = 589,114), we matched ASD cases (n = 4,709) by age and sex to 10 randomly selected controls. We retrieved parental SES measures collected at time of birth by record linkage. RESULTS Children of families with lower income, and of parents with manual occupations (OR = 1.4, 95% CI = 1.3-1.6) were at higher risk of ASD. No important relationships with parental education were observed. These associations were present after accounting for parental ages, migration status, parity, psychiatric service use, maternal smoking during pregnancy, and birth characteristics; and regardless of comorbid intellectual disability. CONCLUSIONS Lower, not higher, socioeconomic status was associated with an increased risk of ASD. Studies finding the opposite may be underestimating the burden of ASD in lower SES groups.

Maternal Effects for Preterm Birth: A Genetic Epidemiologic Study of 630,000 Families

This study was undertaken to disentangle the maternal genetic from the fetal genetic effects for preterm birth and to study the possibility of these effects being explained by known risk factors. By cross-linking of the population-based Swedish Multigeneration and Medical Birth registers, 989,027 births between 1992 and 2004 were identified. Alternating logistic regression was applied to model the familial clustering with pairwise odds ratios (PORs), and covariates were included to evaluate if the familial aggregation was explained by exposure to shared risk factors. Generalized linear mixed models were used to estimate the contribution of genetic and environmental effects. Sisters of women who had a preterm delivery had themselves an increased odds of having a preterm delivery (POR = 1.8, 95% confidence interval: 1.5, 2.1), while there was no corresponding increase in odds in families joined by brothers (POR = 1.1, 95% confidence interval: 0.9, 1.4). Twenty-five percent of the variation in preterm birth was explained by maternal genetic factors, whereas fetal genetic factors only marginally influenced the variation in liability. The increased odds ratio between offspring of sisters was independent of maternal risk factors for preterm birth, suggesting that the relative importance of maternal effects is not explained by these well-known risk factors.

Cohort Profile: The Stockholm Public Health Cohort

The Stockholm Public Health Cohort was set up within the Stockholm County Council public health surveys to inform on determinants and consequences of significant contributors to the current burden of disease. Participants are 89 268 randomly selected individuals from the adult population of Stockholm County. Baseline surveys took place in 2002, 2006 and 2010 via self-administered questionnaires. So far, participants recruited in 2002 were re-surveyed twice, in 2007 and 2010, and those enrolled in 2006 were re-surveyed once, in 2010. Self-reported data are regularly supplemented by information from national and regional health data and administrative registers, for study participants and their relatives (including their offspring). Available data are extensive and include a wide array of health, lifestyle, perinatal, demographic, socio-economic and familial factors. The cohort is an international resource for epidemiological research, and the data available to the research community for specific studies obtained approval from the Stockholm Public Health Cohort Steering Committee and the Stockholm Regional Ethical Review Board.

Migration and autism spectrum disorder: population-based study {

BACKGROUND Migration has been implicated as a risk factor for autism, but evidence is limited and inconsistent. AIMS To investigate the relationship between parental migration status and risk of autism spectrum disorder, taking into consideration the importance of region of origin, timing of migration and possible discrepancies in associations between autism subtypes. METHOD Record-linkage study within the total child population of Stockholm County between 2001 and 2007. Individuals with high- and low-functioning autism were defined as having autism spectrum disorder with and without comorbid intellectual disability, and ascertained via health and habilitation service registers. RESULTS In total, 4952 individuals with autism spectrum disorder were identified, comprising 2855 children with high-functioning autism and 2097 children with low-functioning autism. Children of migrant parents were at increased risk of low-functioning autism (odds ratio (OR) = 1.5, 95% CI 1.3-1.7); this risk was highest when parents migrated from regions with a low human development index, and peaked when migration occurred around pregnancy (OR = 2.3, 95% CI 1.7-3.0). A decreased risk of high-functioning autism was observed in children of migrant parents, regardless of area of origin or timing of migration. Parental age, income or obstetric complications did not fully explain any of these associations. CONCLUSIONS Environmental factors associated with migration may contribute to the development of autism presenting with comorbid intellectual disability, especially when acting in utero. High- and low-functioning autism may have partly different aetiologies, and should be studied separately.

Parental age and the risk of autism spectrum disorders: findings from a Swedish population-based cohort

BACKGROUND The objectives of this study were to examine the independent and dependent associations of maternal and paternal age and risk of offspring autism spectrum disorders (ASD), with and without intellectual disability (ID). METHODS The sample consisted of 417 303 Swedish children born 1984-2003. ASD case status (N = 4746) was ascertained using national and regional registers. Smoothing splines in generalized additive models were used to estimate associations of parental age with ASD. RESULTS Whereas advancing parental age increased the risk of child ASD, maternal age effects were non-linear and paternal age effects were linear. Compared with mothers at the median age 29 years, those <29 had similar risk, whereas risk increased after age 30, with an odds ratio (OR) of 1.75 [95% (CI): 1.63-1.89] at ages 40-45. For fathers, compared with the median age of 32 years, the OR for ages 55-59 was 1.39 (1.29-1.50). The risk of ASD was greater for older mothers as compared with older fathers. For example, mothers aged 40-45 (≥97.2th percentile) had an estimated 18.63 (95% CI: 17.25-20.01) ASD cases per 1000 births, whereas fathers aged 55-59 (≥99.7th percentile) had 16.35 (95% CI: 15.11-17.58) ASD cases per 1000 births. In analyses stratified by co-parental age, increased risk due to advancing paternal age was evident only with mothers ≤35 years. In contrast, advancing maternal age increased risk regardless of paternal age. Advancing parental age was more strongly associated with ASD with ID, compared with ASD without ID. CONCLUSIONS We confirm prior findings that advancing parental age increases risk of ASD, particularly for ASD with ID, in a manner dependent on co-parental age. Although recent attention has emphasized the effects of older fathers on ASD risk, an increase of n years in maternal age has greater implications for ASD risk than a similar increase in paternal age.

Deviance in Fetal Growth and Risk of Autism Spectrum Disorder

OBJECTIVE Understanding the relationship between fetal growth and autism spectrum disorder (ASD) is likely to advance the search for genetic and nongenetic causes of ASD. The authors explored the associations between fetal growth, gestational age, and ASD with and without comorbid intellectual disability in a Scandinavian study population. METHOD The authors conducted a matched nested case-control study within the Stockholm Youth Cohort that included all children ages 0-17 who resided in Stockholm County from 2001 to 2007 (N=589,114). The authors identified 4,283 children with ASD: 1,755 with intellectual disability and 2,528 without, and they selected 36,588 age- and sex-matched comparison subjects. ASD case subjects were ascertained from unique identifiers assigned to all Swedish residents and linkage with official registers covering all pathways of assessment or care of ASD in Stockholm County. The authors calculated z scores of deviance in fetal growth from a reference curve using records from the national Swedish Medical Birth Registry, which included ultrasound dating of gestational age as well as birth weight. Crude and adjusted odds ratios for ASD, ASD with intellectual disability, and ASD without intellectual disability were the main outcome measures. RESULTS ASD risk increased with fetal growth 1.50 standard deviations below and >2.00 standard deviations above the mean for gestational age; the greatest risk was for fetal growth that was less than 2.00 standard deviations below the mean (adjusted odds ratio=1.70; 95% CI=1.44-2.01) or greater than 2.00 standard deviations above the mean (adjusted odds ratio=1.50; 95% CI=1.27-1.77). The same overall pattern was observed for ASD with and without intellectual disabilities. However, poor fetal growth (i.e., growth below the mean) was more strongly associated with ASD with intellectual disabilities than without. Regardless of fetal growth, preterm birth increased ASD risk. CONCLUSIONS Deviance in fetal growth at either distributional extreme may be a significant antecedent to the development of ASD through genetic and/or nongenetic mechanisms.

Fertility of first-degree relatives of patients with schizophrenia: A three generation perspective

We explored the fertility in three generations; fertility of parents, siblings and offspring to patients with schizophrenia, to test the hypothesis that the decreased reproductive rate in the patients is compensated by an increased rate in their first-degree relatives. A population-based national database was created by linking the Swedish Multi-Generation and Hospital Discharge Registers. To maximize follow-up time for schizophrenia and reproductive history, three birth cohorts were selected: parental generation, born 1918-1927 (n=274464); affected generation, born 1932-1941 (n=108502) and offspring to affected generation, born 1951-1960 (n=103105). Ratios of estimated mean number of offspring were measured (fertility ratios), comparing the study subjects to the general population. The fertility among males with schizophrenia was decreased by over 70% (fertility ratio(patients/population)=0.29, 95% CI 0.25-0.35), whereas female patients had less than half as many offspring as the general female population (fertility ratio(patients/population)=0.48, 95% CI 0.42-0.55). When accounting for selection bias of larger families, no statistically significant difference was found among parents of patients with and without a diagnosis of schizophrenia. Further, the fertility among siblings of schizophrenic patients did not differ from the general population. A reduction in fertility was found among offspring to patients with schizophrenia, male offspring had 12% fewer offspring (fertility ratio(offspring/population)=0.88, 95%CI 0.77-1.01), while female offspring had 6% fewer offspring (fertility ratio(offspring/population)=0.94, 95% CI 0.84-1.05). In conclusion, we found reduced fertility in patients with schizophrenia and among their offspring that was not compensated by higher parental or sibling fertility.

Brief Report: Maternal Smoking during Pregnancy and Autism Spectrum Disorders.

Prenatal exposure to tobacco smoke is suggested as a potential risk factor for autism spectrum disorders (ASD). Previous epidemiological studies of this topic have yielded mixed findings. We performed a case–control study of 3,958 ASD cases and 38,983 controls nested in a large register-based cohort in Sweden. ASD case status was measured using a multisource case ascertainment system. In adjusted results, we found that maternal smoking during pregnancy is not associated with increased risk of ASD regardless of presence or absence of comorbid intellectual disability. Apparent associations were attributable to confounding by sociodemographic characteristics of parents such as education, income, and occupation.

Fetal and Maternal Genes’ Influence on Gestational Age in a Quantitative Genetic Analysis of 244,000 Swedish Births

Although there is increasing evidence that genetic factors influence gestational age, it is unclear to what extent this is due to fetal and/or maternal genes. In this study, we apply a novel analytical model to estimate genetic and environmental contributions to pregnancy history records obtained from 165,952 Swedish families consisting of offspring of twins, full siblings, and half-siblings (1987-2008). Results indicated that fetal genetic factors explained 13.1% (95% confidence interval (CI): 6.8, 19.4) of the variation in gestational age at delivery, while maternal genetic factors accounted for 20.6% (95% CI: 18.1, 23.2). The largest contribution to differences in the timing of birth were environmental factors, of which 10.1% (95% CI: 7.0, 13.2) was due to factors shared by births of the same mother, and 56.2% (95% CI: 53.0, 59.4) was pregnancy specific. Similar models fit to the same data dichotomized at clinically meaningful thresholds (e.g., preterm birth) resulted in less stable parameter estimates, but the collective results supported a model of homogeneous genetic and environmental effects across the range of gestational age. Since environmental factors explained most differences in the timing of birth, genetic studies may benefit from understanding the specific effect of fetal and maternal genes in the context of these yet-unidentified factors.