Sven Sandin

The Familial Risk of Autism

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.

Most genetic risk for autism resides with common variation

A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (herein termed autism), the nature of the allelic spectrum is uncertain. Individual risk-associated genes have been identified from rare variation, especially de novo mutations. From this evidence, one might conclude that rare variation dominates the allelic spectrum in autism, yet recent studies show that common variation, individually of small effect, has substantial impact en masse. At issue is how much of an impact relative to rare variation this common variation has. Using a unique epidemiological sample from Sweden, new methods that distinguish total narrow-sense heritability from that due to common variation and synthesis of results from other studies, we reach several conclusions about autisms genetic architecture: its narrow-sense heritability is ∼52.4%, with most due to common variation, and rare de novo mutations contribute substantially to individual liability, yet their contribution to variance in liability, 2.6%, is modest compared to that for heritable variation.

Advancing Paternal Age and Risk of Autism New Evidence from a Population-Based Study and a Meta-Analysis of Epidemiological Studies.

Advanced paternal age has been suggested as a risk factor for autism, but empirical evidence is mixed. This study examines whether the association between paternal age and autism in the offspring (1) persists controlling for documented autism risk factors, including family psychiatric history, perinatal conditions, infant characteristics and demographic variables; (2) may be explained by familial traits associated with the autism phenotype, or confounding by parity; and (3) is consistent across epidemiological studies. Multiple study methods were adopted. First, a Swedish 10-year birth cohort (N=1 075 588) was established. Linkage to the National Patient Register ascertained all autism cases (N=883). Second, 660 families identified within the birth cohort had siblings discordant for autism. Finally, meta-analysis included population-based epidemiological studies. In the birth cohort, autism risk increased monotonically with increasing paternal age. Offspring of men aged ⩾50 years were 2.2 times (95% confidence interval: 1.26–3.88: P=0.006) more likely to have autism than offspring of men aged ⩽29 years, after controlling for maternal age and documented risk factors for autism. Within-family analysis of discordant siblings showed that affected siblings had older paternal age, adjusting for maternal age and parity (P<0.0001). Meta-analysis demonstrated advancing paternal age association with increased risk of autism across studies. These findings provide the strongest evidence to date that advanced paternal age is a risk factor for autism in the offspring. Possible biological mechanisms include de novo aberration and mutations or epigenetic alterations associated with aging.

Advancing Paternal Age and Bipolar Disorder

CONTEXT Advancing paternal age has been reported as a risk factor for neurodevelopmental disorders. OBJECTIVES To determine whether advanced paternal age is associated with an increased risk of BPD in the offspring and to assess if there was any difference in risk when analyzing patients with early-onset BPD separately. DESIGN A nationwide nested case-control study based on Swedish registers was performed. Risk for BPD in the offspring of older fathers was estimated using conditional logistic regression analysis controlling for potential confounding of parity, maternal age, socioeconomic status, and parental family history of psychotic disorders. SETTING Identification of 7,328,100 individuals and their biological parents by linking the nationwide Multigeneration Register and the Hospital Discharge Register. PARTICIPANTS A total of 13,428 patients with a BPD diagnosis on at least 2 separate hospital admissions was identified. Five healthy control subjects matched for sex and year of birth were randomized to each case. Main Outcome Measure Bipolar disorder based on ICD codes at discharge from hospital treatment. RESULTS An association between paternal age and risk for BPD in the offspring of older men was noted. The risk increased with advancing paternal age. After controlling for parity, maternal age, socioeconomic status, and family history of psychotic disorders, the offspring of men 55 years and older were 1.37 (95% confidence interval [CI], 1.02-1.84) times more likely to be diagnosed as having BPD than the offspring of men aged 20 to 24 years. The maternal age effect was less pronounced. For early-onset (<20 years) cases, the effect of paternal age was much stronger (odds ratio, 2.63; 95% CI, 1.19-5.81), whereas no statistically significant maternal age effect was found. CONCLUSIONS Advanced paternal age is a risk factor for BPD in the offspring. The results are consistent with the hypothesis that advancing paternal age increases the risk for de novo mutations in susceptibility genes for neurodevelopmental disorders.

Advancing Maternal Age Is Associated With Increasing Risk for Autism: A Review and Meta-Analysis

OBJECTIVE We conducted a meta-analysis of epidemiological studies investigating the association between maternal age and autism. METHOD Using recommended guidelines for performing meta-analyses, we systematically selected, and extracted results from, epidemiological scientific studies reported before January 2012. We calculated pooled risk estimates comparing categories of advancing maternal age with and without adjusting for possible confounding factors. We investigated the influence of gender ratio among cases, ratio of infantile autism to autism spectrum disorder (ASD), and median year of diagnosis as effect moderators in mixed-effect meta-regression. RESULTS We found 16 epidemiological papers fulfilling the a priori search criteria. The meta-analysis included 25,687 ASD cases and 8,655,576 control subjects. Comparing mothers ≥ 35 years with mothers 25 to 29 years old, the crude relative risk (RR) for autism in the offspring was 1.52 (95% confidence interval [CI] = 1.12-1.92). Comparing mothers ≥ 35 with mothers 25-29, [corrected] the adjusted relative risk (RR) for autism in the offspring was 1.31 (95% CI = 1.19-1.45). [corrected] For mothers <20 compared with mothers 25 to 29 years old, there was a statistically significant decrease in risk (RR = 0.76; 95% confidence interval = 0.60-0.97). Almost all studies showed a dose-response effect of maternal age on risk of autism. The meta-regression suggested a stronger maternal age effect in the studies with more male offspring and for children diagnosed in later years. CONCLUSIONS The results of this meta-analysis support an association between advancing maternal age and risk of autism. The RR increased monotonically with increasing maternal age. The association persisted after the effects of paternal age and other potential confounders had been considered, supporting an independent relation between higher maternal age and autism.

Low carbohydrate-high protein diet and incidence of cardiovascular diseases in Swedish women: prospective cohort study.

Objective To study the long term consequences of low carbohydrate diets, generally characterised by concomitant increases in protein intake, on cardiovascular health. Design Prospective cohort study. Setting Uppsala, Sweden. Participants From a random population sample, 43 396 Swedish women, aged 30-49 years at baseline, completed an extensive dietary questionnaire and were followed-up for an average of 15.7 years. Main outcome measures Association of incident cardiovascular diseases (ascertained by linkage with nationwide registries), overall and by diagnostic category, with decreasing carbohydrate intake (in tenths), increasing protein intake (in tenths), and an additive combination of these variables (low carbohydrate-high protein score, from 2 to 20), adjusted for intake of energy, intake of saturated and unsaturated fat, and several non-dietary variables. Results A one tenth decrease in carbohydrate intake or increase in protein intake or a 2 unit increase in the low carbohydrate-high protein score were all statistically significantly associated with increasing incidence of cardiovascular disease overall (n=1270)—incidence rate ratio estimates 1.04 (95% confidence interval 1.00 to 1.08), 1.04 (1.02 to 1.06), and 1.05 (1.02 to 1.08). No heterogeneity existed in the association of any of these scores with the five studied cardiovascular outcomes: ischaemic heart disease (n=703), ischaemic stroke (n=294), haemorrhagic stroke (n=70), subarachnoid haemorrhage (n=121), and peripheral arterial disease (n=82). Conclusions Low carbohydrate-high protein diets, used on a regular basis and without consideration of the nature of carbohydrates or the source of proteins, are associated with increased risk of cardiovascular disease.

Mediterranean dietary pattern and mortality among young women: a cohort study in Sweden

Studies of diet and health focus increasingly on dietary patterns. Although the traditional Mediterranean diet is perceived as being healthy, there is little information on its possible benefit to young people. We studied whether closer adherence to the traditional Mediterranean dietary pattern was associated with overall and cancer mortality in a cohort of 42,237 young women, aged 30-49 years at enrollment, who were recruited in 1991-2 from the general population in the Uppsala Health Care Region, Sweden, and followed up, almost completely, for about 12 years. Adherence to the Mediterranean diet was assessed by a 10-point score incorporating the characteristics of this diet. Among women less than 40 years old at enrollment--whose causes of death are mainly cancer with probable genetic influences, injuries or suicide--there was no association of the Mediterranean diet score with total or cancer mortality. Among women 40-49 years old at enrollment, a 2-point increase in the score was associated with considerable reductions in overall mortality (13%; 95% CI 1%, 23%; P approximately 0.05) and cancer mortality (16%; 95% CI -1%, 29%; P approximately 0.06). Few cardiovascular deaths occurred in this cohort of young women. The findings of the present study in a northern European population of young women indicate that closer adherence to a Mediterranean dietary pattern reduces mortality even among young persons.

Low carbohydrate-high protein diet and mortality in a cohort of Swedish women

Objective.  The long‐term health consequences of diets used for weight control are not established. We have evaluated the association of the frequently recommended low carbohydrate diets – usually characterized by concomitant increase in protein intake – with long‐term mortality.

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.

Autism and Mental Retardation Among Offspring Born After In Vitro Fertilization

IMPORTANCE Between 1978 and 2010, approximately 5 million infants were born after in vitro fertilization (IVF) treatments. Yet limited information on neurodevelopment after IVF exists, especially after the first year of life. OBJECTIVE To examine the association between use of any IVF and different IVF procedures and the risk of autistic disorder and mental retardation in the offspring. DESIGN, SETTING, AND PARTICIPANTS A population-based, prospective cohort study using Swedish national health registers. Offspring born between 1982 and 2007 were followed up for a clinical diagnosis of autistic disorder or mental retardation until December 31, 2009. The exposure of interest was IVF, categorized according to whether intracytoplasmic sperm injection (ICSI) for male infertility was used and whether embryos were fresh or frozen. For ICSI, whether sperm were ejaculated or surgically extracted was also considered. MAIN OUTCOMES AND MEASURES Relative risks (RRs) for autistic disorder and mental retardation and rates per 100,000 person-years, comparing spontaneously conceived offspring with those born after an IVF procedure and comparing 5 IVF procedures used in Sweden vs IVF without ICSI with fresh embryo transfer, the most common treatment. We also analyzed the subgroup restricted to singletons. RESULTS Of the more than 2.5 million infants born, 30,959 (1.2%) were conceived by IVF and were followed up for a mean 10 (SD, 6) years. Overall, 103 of 6959 children (1.5%) with autistic disorder and 180 of 15,830 (1.1%) with mental retardation were conceived by IVF. The RR for autistic disorder after any procedure compared with spontaneous conception was 1.14 (95% CI, 0.94-1.39; 19.0 vs 15.6 per 100,000 person-years). The RR for mental retardation was 1.18 (95% CI, 1.01-1.36; 46.3 vs 39.8 per 100,000 person-years). For both outcomes, there was no statistically significant association when restricting analysis to singletons. Compared with IVF without ICSI with fresh embryo transfer, there were statistically significantly increased risks of autistic disorder following ICSI using surgically extracted sperm and fresh embryos (RR, 4.60 [95% CI, 2.14-9.88]; 135.7 vs 29.3 per 100,000 person-years); for mental retardation following ICSI using surgically extracted sperm and fresh embryos (RR, 2.35 [95% CI, 1.01-5.45]; 144.1 vs 60.8 per 100,000 person-years); and following ICSI using ejaculated sperm and fresh embryos (RR, 1.47 [95% CI, 1.03-2.09]; 90.6 vs 60.8 per 100,000 person-years). When restricting the analysis to singletons, the risks of autistic disorder associated with ICSI using surgically extracted sperm were not statistically significant, but the risks associated with ICSI using frozen embryos were significant for mental retardation (with frozen embryos, RR, 2.36 [95% CI, 1.04-5.36], 118.4 vs 50.6 per 100,000 person-years]; with fresh embryos, RR, 1.60 [95% CI, 1.00-2.57], 80.0 vs 50.6 per 100,000 person-years). CONCLUSIONS AND RELEVANCE Compared with spontaneous conception, IVF treatment overall was not associated with autistic disorder but was associated with a small but statistically significantly increased risk of mental retardation. For specific procedures, IVF with ICSI for paternal infertility was associated with a small increase in the RR for autistic disorder and mental retardation compared with IVF without ICSI. The prevalence of these disorders was low, and the increase in absolute risk associated with IVF was small.