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Cited by 683Autism Spectrum Disorder ResearchGenetic Associations and EpidemiologyGenetics and Neurodevelopmental Disorders

Association of Genetic and Environmental Factors With Autism in a 5-Country Cohort

Open access
Bai, Dan, Yip, Benjamin Hon Kei, Windham, Gayle C., Sourander, Andre, Francis, Richard, Yoffe, Rinat, Glasson, Emma, Mahjani, Behrang +14 more·2019·JAMA Psychiatry
DOI 10.1001/jamapsychiatry.2019.1411PMC PMC6646998
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Abstract

Importance: The origins and development of autism spectrum disorder (ASD) remain unresolved. No individual-level study has provided estimates of additive genetic, maternal, and environmental effects in ASD across several countries. Objective: To estimate the additive genetic, maternal, and environmental effects in ASD. Design, Setting, and Participants: Population-based, multinational cohort study including full birth cohorts of children from Denmark, Finland, Sweden, Israel, and Western Australia born between January 1, 1998, and December 31, 2011, and followed up to age 16 years. Data were analyzed from September 23, 2016 through February 4, 2018. Main Outcomes and Measures: Across 5 countries, models were fitted to estimate variance components describing the total variance in risk for ASD occurrence owing to additive genetics, maternal, and shared and nonshared environmental effects. Results: The analytic sample included 2 001 631 individuals, of whom 1 027 546 (51.3%) were male. Among the entire sample, 22 156 were diagnosed with ASD. The median (95% CI) ASD heritability was 80.8% (73.2%-85.5%) for country-specific point estimates, ranging from 50.9% (25.1%-75.6%) (Finland) to 86.8% (69.8%-100.0%) (Israel). For the Nordic countries combined, heritability estimates ranged from 81.2% (73.9%-85.3%) to 82.7% (79.1%-86.0%). Maternal effect was estimated to range from 0.4% to 1.6%. Estimates of genetic, maternal, and environmental effects for autistic disorder were similar with ASD. Conclusions and Relevance: Based on population data from 5 countries, the heritability of ASD was estimated to be approximately 80%, indicating that the variation in ASD occurrence in the population is mostly owing to inherited genetic influences, with no support for contribution from maternal effects. The results suggest possible modest differences in the sources of ASD risk between countries.

AI snapshot

Written from the paper’s full text.

TL;DR

In a population-based 5-country cohort of 2,001,631 children, ASD heritability was estimated at approximately 80%, with no support for maternal effects and minimal shared environmental contribution; nonshared environment accounted for the remainder. Estimates varied modestly by country, with lower heritability and higher shared environment in Finland and Western Australia.

Key findings

  • The analytic sample included 2,001,631 children from 680,502 families; 1,027,546 (51.3%) were male, and 22,156 (1.11%) were diagnosed with ASD (Denmark, 7,580; Finland, 2,968; Sweden, 10,563; Israel, 490; Western Australia, 555).
  • Median ASD heritability was 80.8% (95% CI, 73.2%-85.5%) for country-specific point estimates, ranging from 50.9% (25.1%-75.6%) in Finland to 86.8% (69.8%-100.0%) in Israel. For the Nordic countries combined, heritability estimates ranged from 81.2% (73.9%-85.3%) to 82.7% (79.1%-86.0%) across models.
  • Maternal effect was estimated to range from 0.4% to 1.6% in country-specific ACME models; the Nordic pooled estimate was 0.5%, and all 95% CIs included zero. Shared environment was generally minimal: Nordic pooled estimates were 0.2% to 0.3%, with CIs including zero, though Finland (ACE, 14.5%) and Western Australia (ACE, 25.2%) showed higher shared environmental estimates.
  • Nonshared environment estimates were 17.3% (14.0%-20.9%) for the Nordic AE model, 17.7% (13.9%-26.5%) for ACE, and 18.1% (14.1%-21.7%) for ACME; country-specific estimates ranged from 15.1% to 33.6% depending on model. Results for autistic disorder were similar to those for ASD.

Methods

  • Population-based, multinational cohort study using full birth cohorts from Denmark, Finland, Sweden, Israel, and Western Australia. Denmark, Finland, Sweden, and Western Australia included births from January 1, 1998, to December 31, 2007; Israel included births from January 1, 2000, to December 31, 2011. Individuals were followed for ASD diagnosis up to age 16 years via government-maintained national health registries; multiple births/twins were excluded, and half siblings were excluded from the main analysis.
  • Three-generational family linkages identified parents, siblings, and cousins. Liability threshold models decomposed variance in ASD liability into additive genetic (A), maternal (M), shared environmental (C), and nonshared environmental (E) components. Three nested models were fitted: AE, ACE, and ACME. Full siblings, cousins, and maternal parallel cousins were used; 95% CIs were calculated using profile likelihood methods; sex and birth-year cohort were fixed factors; a pooled Nordic analysis combined Denmark, Finland, and Sweden.
  • Analyses used ViPAR running R statistical software; data were analyzed from September 23, 2016, through February 4, 2018.

Limitations

  • The paper states that despite the large overall sample, effective sample size for individual countries was limited by the low prevalence of ASD. It also notes potential misspecification from unmodeled gene-environment correlation or interaction, which could bias heritability estimates; possible health-care-seeking differences by sibling sex composition; possible upward bias of the M component from misspecification of C and M, though M estimates were near zero; reliance on the assumption of independent ascertainment; and exclusion of twins because zygosity was unavailable and twins have elevated ASD risk.
  • Evident in the text: diagnostic systems differed across sites and were harmonized; Israel contributed only ASD analyses because autistic disorder diagnosis was unavailable; Finland and Western Australia had small numbers of concordant cousin pairs and predominantly younger-age ascertainment; sensitivity analyses suggested that random underascertainment may underestimate true heritability and increase the observed shared environment component.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1001/jamapsychiatry.2019.1411

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 41 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In this study's estimates, the maternal effect showed no or only minimal association with variation in risk for ASD and for autistic disorder.

    “When we estimated the maternal effect, however, its association with variation in risk for ASD (and AD) was nonexistent or minimal.”
    • Also stated in: § Discussion · hedged
      “The absence of M effects indicates that there is no strong evidence of a maternal effect, driven by genetic factors shared between sisters, associated with the risk of ASD.”
    Quote in the paperSubstantial claim
  • Findingown data

    The pooled estimates for ASD were identical to those for autistic disorder.

    “The pooled estimates for ASD were the same as for AD.”
    Quote in the paperNot a substantial claim
  • Interpretationown data

    Nonshared environmental factors consistently contribute to ASD risk.

    “Nonshared environmental factors also consistently contribute to risk.”
    Quote in the paperSubstantial claim
  • Interpretationown data

    The findings hint at small country-to-country differences in what contributes to ASD risk.

    “The results suggest possible modest differences in the sources of ASD risk between countries.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Noninherited genetic factors may contribute to trait variation.

    “However, evidence shows that there are other, noninherited, genetic influences that could be associated with variation in a trait.3”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] source

      Not checked in the free run.

  • May combine two claims. 36
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Findingown data

    Country-specific nonshared environmental effect estimates ranged from 16.0% to 19.3% in AE, 15.1% to 32.8% in ACE, and 17.5% to 33.6% in ACME; Nordic pooled estimates were 17.3% (AE), 17.7% (ACE), and 18.1% (ACME).

    “Country-specific point estimates for nonshared environmental effects ranged between 16.0% (95% CI, 11.9%-20.4%)(Sweden) and 19.3% (95% CI, 14.6%-25.9%)(Denmark) in the AE model; 15.1% (95% CI, 11.1%-21.1%)(Sweden) and 32.8% (95% CI, 17.6%-51.1%)(Finland) in the ACE model; and 17.5% (95% CI, 12.5%-22.5%)(Sweden); and 33.6% (95% CI, 17.6%-53.9%)(Finland) for the ACME model.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Among the analytic sample, 22,156 children (1.11%) were diagnosed with ASD, with country-specific counts Denmark 7580, Finland 2968, Sweden 10563, Israel 490, and Western Australia 555.

    “Of these, 22 156 (1.11%) children were diagnosed with ASD (Denmark, 7580; Finland, 2968; Sweden, 10 563; Israel, 490; Western Australia, 555) (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For Israel, the ACE-model additive genetic effect was 86.8% (95% CI 69.8-100.0), similar to Denmark and Sweden; for Western Australia it was 53.8% (28.5-74.3), resembling Finland.

    “Results for Israel for additive genetic effect (86.8% [95% CI, 69.8%-100.0%])were similar to those from Denmark and Sweden, whereas results from Western Australia resembled those from Finland (additive genetic effect 53.8% [28.5%, 74.3%]) (Table 3; eFigure 6 in the Supplement).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The analytic sample comprised 2,001,631 children from 680,502 families, of whom 1,027,546 (51.3%) were male, followed up to age 16 years.

    “The analytic sample included 2 001 631 children, of whom 1 027 546 (51.3%) were male, from 680 502 families followed up to age 16 years.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the three-Nordic-country models, the lower 95% CI bound for genetic factors was 73.9% of risk variability, and the upper bound for nonshared environment was 26.5%.

    “In the models that combined data from the 3 Nordic countries, the genetic factors explained at least 73.9 % of the variability in risk, and nonshared environment at most 26.5% based on the lower and upper bounds of the respective 95% CIs.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Danish, Finnish, and Swedish health, ascertainment, and diagnostic systems are alike.

  • May combine two claims.

    Findingown data

    For autistic disorder, additive genetic effect estimates under the ACE model were 84.6% (Denmark), 72.7% (Finland), and 76.3% (Sweden); maternal effect for the Nordic combined sample was 0.6%; nonshared environment estimates were 15.1% (Denmark), 16.7% (Finland), and 21.9% (Sweden).

    “Estimates of genetic, maternal, and environmental effects were similar with ASD; additive genetic effect, ACE model: 84.6% (95% CI, 69.7%-88.7%)(Denmark), 72.7% (95% CI, 54.2%-81.0%)(Finland), 76.3% (95% CI, 62.3%-83.0%)(Sweden); maternal effects for the Nordic combined sample, 0.6% (95% CI, 0.0%-4.9%),and nonshared environment ACE model, 15.1% (95% CI, 10.6%-21.5%)(Denmark), 16.7% (95% CI, 13.0%-”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The median country-specific ASD heritability estimate was 80.8% (95% CI, 73.2%-85.5%), ranging from 50.9% (Finland) to 86.8% (Israel).

    “The median (95% CI) ASD heritability was 80.8% (73.2%-85.5%)for country-specific point estimates, ranging from 50.9% (25.1%-75.6%)(Finland) to 86.8% (69.8%-100.0%)(Israel).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In a simulation reducing Swedish ASD prevalence to approximate Finland's (6.91 vs 6.89 cases per 1000), the heritability estimate was 62.0% (95% CI 54.1-70.9), closer to Finland's 50.9%, but shared environmental effect was 0.7% (95% CI 0.0-6.8) versus Finland's 14.0% (95% CI 0.0-28.6).

    “The heritability estimate from this simulation was more similar to that of Finland (simulation: 62.0% [95% CI, 54.1%- 70.9%] vs Finland above, 50.9% [95% CI, 25.1%-75.6%]), but the shared environmental effect was 0.7% (95% CI, 0.0%- 6.8%) compared with Finland (14.0% [95% CI, 0.0%-28.6%]) (eTable 6 in the Supplement).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For the Nordic countries combined, heritability estimates were 82.7% (95% CI 79.1-86.0) for AE, 82.2% (77.2-85.9) for ACE, and 81.2% (73.9-85.3) for ACME.

    “The heritability estimates for the Nordic pooled sample were 82.7% (95% CI, 79.1%-86.0%)for the AE, 82.2% (77.2%-85.9%)for the ACE model, and 81.2% (95% CI, 73.9%-85.3%)for the ACME model (Table 2; Figure 2).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Danish, Finnish, and Swedish health, ascertainment, and diagnostic systems are alike.

  • May combine two claims.

    Findingown data

    Compared with the other countries, Finland and Western Australia had lower heritability and a larger shared-environment contribution to ASD.

    “Because Finland and Western Australia showed reduced heritability estimates and an increased contribution from shared environment to ASD compared with the remaining countries (Table 2, eFigure 6 in the Supplement), we executed a series of sensitivity analyses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Country-specific shared environmental effect estimates ranged from 0.0% to 14.5% in the ACE model and from 0.0% to 14.0% in the ACME model; Nordic pooled estimates were 0.2% (ACE) and 0.3% (ACME), with CIs including zero.

    “Country-specific point estimates of shared environmental effects ranged between 0.0% (95% CI, 0.0%-4.6%)(Den- mark) and 14.5% (95% CI, 4.5%-29.2%)(Denmark) in the ACE model and 0.0% (95% CI, 0.0%-3.7%)(Sweden) and 14.0% (95% CI, 0.0%-28.6%)(Finland) in the ACME model.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cumulative diagnosis probability for ASD and AD rose similarly with age in Denmark and Sweden, while Western Australia and Finland ascertained cases mainly at younger ages.

    “Denmark and Sweden both have similar increasing cumulative prob- ability of ASD and AD up to age 16 years, whereas the ascer- tainment in Western Australia and Finland is predominantly at younger ages (ASD, eFigure 10 in the Supplement; AD, eFigure 11 in the Supplement).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Country-specific point estimates of narrow-sense heritability for ASD ranged from 80.7% (Denmark) to 84.1% (Sweden) under AE, from 52.8% (Finland) to 84.8% (Sweden) under ACE, and from 50.9% (Finland) to 81.1% (Sweden) under ACME.

    “Country-specific point estimates of additive genetic effect (narrow-sense heritability) ranged between 80.7% (95% CI, 74.1%-85.4%)(Denmark) and 84.1% (95% CI, 79.7%-88.1%)(Sweden) for the AE model; 52.8% (95% CI, 29.7%-76.3%)(Finland) and 84.8% (95% CI, 76.2%-88.7%)(Sweden) for the ACE model; and 50.9% (95% CI, 25.1%-75.6%)(Finland) and 81.1% (95% CI, 69.9%-86.7%)(Sweden) for the ACME model.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Country-specific maternal effect estimates ranged from 0.4% to 1.6% in the ACME model, and the Nordic pooled estimate was 0.5%, with all 95% CIs including zero.

    “Country-specific point estimates of maternal effects ranged between 0.4% and 1.6% in the ACME model, and the Nordic pooled sample estimate was 0.5%, but in all models the 2-sided 95% CIs included zero (Table 2; eFigure 12 in the Supplement).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Shared environmental influences were not supported in the two largest samples, Denmark and Sweden, but were supported in Finland and Western Australia.

    “Although the 2 largest samples (Denmark, Sweden) did not support shared environmental influences, 2 other samples (Finland, Western Australia) did.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Shared environmental factors made only a small contribution to ASD risk overall, as in most other studies.

    “Like most studies, 8,11 overall shared environmental factors contributed minimally to the risk of ASD.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] source

      Not checked in the free run.

    • cites [11] source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In this largest study to date, based on population data from five countries, the heritability of ASD was estimated at about 80%, indicating that population variation in ASD occurrence is mostly due to inherited genetic influences, with no support for a maternal contribution.

    “Based on population data from 5 countries, in what is to our knowledge the largest study to date, the heritability of ASD was estimated to be approximately 80%, indicating that the variation in ASD occurrence in the population is mostly owing to inherited genetic influences, with no support for contribution from maternal effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Results from Israel resembled those from Denmark and Sweden, while results from Western Australia resembled those from Finland.

    “Results for Israel were similar to those from Denmark and Sweden, whereas results from Western Australia resembled those from Finland.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In most analyses, results for autistic disorder and ASD were alike: additive genetic effects had the largest influence on liability, followed by nonshared environment, with little evidence of maternal or shared environment effects.

    “In the bulk of the analyses, results for AD and ASD were similar: additive genetic effects accounted for the largest influence on liability, followed by contribution from nonshared environment, with little evidence for maternal or shared environment effects.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Study design and conductown data

    Within countries, sibling and cousin pairs were comparable on sex ratio, AD proportion, family size, and age spacing.

    “In the analytic sample, com- parisons across countries showed that siblings and cousins were similar with respect to sex ratio, AD proportion (percentage of ASD), family size, and differences in age between sibling or cousin pairs (eTable 11 in the Supplement).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Siblings and cousins did not differ on parental age, interpregnancy interval, parental education, or parental psychiatric history.

    “Similarly, compari- sons did not reveal any differences between siblings and cousins with respect to parental age, interpregnancy inter- val, parental education, or parental psychiatric history (eTable 10 in the Supplement).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The sensitivity analyses suggest that if cases are randomly missed, heritability may be underestimated and the shared-environment component overestimated.

    “Taken together, the sensitivity analyses indicate that a random underascertainment of cases may underestimate the true heritability and increase the observed shared environment component.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nongenetic research often implicates family-member-specific environmental exposures, termed nonshared environment, with cesarean delivery as an example.

    “Research on nongenetic origins has frequently pointed to a role for environmental exposures unique to different family members (nonshared environment), an example of which is cesarean delivery.7”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Across the five countries, ASD heritability was about 80%, which the authors interpret as most population variation in ASD being due to inherited genetic factors and as showing no maternal-effect contribution.

    “Based on population data from 5 countries, the heritability of ASD was estimated to be approximately 80%, indicating that the variation in ASD occurrence in the population is mostly owing to inherited genetic influences, with no support for contribution from maternal effects.”
    • Also stated in: § Discussion · hedged
      “The current study results provide the strongest evidence to our knowledge to date that the majority of risk for ASD is from genetic factors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Reported shared-environment contributions to ASD vary from 7% to 35%, although several studies find zero.

    “Estimates of the contribution of shared environment range from 7% to 35%, 8 but multiple studies estimate the contribution to be zero.4,9,11,12”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [8] source

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  • May combine two claims.

    Premisecitation

    Of the earlier twin and family heritability studies, only one estimated maternal effects and found at most a modest ASD contribution.

    “Among those earlier heritability calculations from twin and family studies (eTable 1 in the Supplement), a single study has estimated maternal effects, 4 reporting modest, if any, contribution to ASD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning

    Misspecification of the shared environment and maternal components will bias the maternal component upward, because the maternal effect is the only sibling-type-specific effect.

    “Furthermore, misspecification of C and M will cause an upward bias of the M component because the M effect is the only effect that is siblingtype specific (correlation of M is only present in the sister-sister pair and absent in other sibling pairs).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    Twins were excluded from the calculations because zygosity status was unavailable and twins are known to have an elevated risk of being diagnosed with ASD.

    “However, because we did not have information about zygosity status and because twins are well known to have an el-evated risk of being diagnosed with ASD 15 we excluded twins from our calculations.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    Any study that uses differences in ASD occurrence between sibling pairs depends on independent ascertainment; if ascertainment is not independent, pairs become more alike and the additive genetic and shared environment contributions may be inflated.

    “Any study using differences in ASD occurrence between sibling pairs will rely on the assumption of independent ascertainment.Lack of independence will make pairs more similar and may therefor inflate the contribution from the additive genetic effect as well as shared environment.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Ascertainment of ASD in sibling pairs is independent.

  • May combine two claims.

    Study design and conductcitation

    The validity and reliability of registry-based diagnoses, and case ascertainment, were reported in earlier publications.

    “Case ascertainment and reliability and validity of registry-reported diagnoses have been published previously.15,16”
    Quote in the paperSubstantial claim0 of 2 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    Instead of assuming asymptotic normality, the authors obtained two-sided 95% CIs by profile likelihood.

    “To calculate CIs, instead of relying on the assumption that estimates follow an asymptotic normal distribution, we calculated 2-sided 95% CIs using profile likelihood methods.23”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] source

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  • May combine two claims.

    Study design and conductreasoning

    Following all participants from birth through population registers avoids bias from self-report and retrospective data collection and reduces selection bias related to disease status or factors such as parental education.

    “This approach, following all participants from birth using population registers, avoids bias owing to self-report and retrospective collection of data and reduces selection biases owing to disease status or factors such as parental education.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Earlier work has applied liability models with full siblings and cousins to estimate additive genetic, shared environmental, and nonshared environmental effects for other outcomes.

    “Liability models using full siblings and cousins to estimate A, C, and E have been used earlier and for other outcomes (eg, skin cancer, 18,19 M component on preterm birth 5 and preeclampsia, 20,21 and comorbidity of 2 diseases).22”
    Quote in the paperSubstantial claim0 of 5 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Plotted likelihood functions indicated that the data supported estimation of the variance components and their two-sided 95% CIs.

    “The plotted likelihood func- tions for the ACE model show the support in the data for es- timating the variance components and the 2-sided 95% CIs (eFigure 16 in the Supplement).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Contribution from shared environmental exposures that make family members similar has been uncertain.

    “In contrast, contribution from environmental exposures that make family members similar (ie, shared environment), has been uncertain.8”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] source

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  • May combine two claims.

    Study design and conductcitation

    A possible violation of the independence of genetic and environmental factors is one source of misspecification; if that correlation is not modeled, its components are largely absorbed into the genetic variance estimate, which may bias the heritability estimate.

    “The first potential misspecification arises from the possible violation of the assumption of independence between genetic and environment.If this correlation is not specifically included in the model, its components will mostly be incorporated into the estimate of genetic variance component, potentially biasing the heritability estimate.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36]

      Not checked in the free run.

    • The authors state this as an assumption: Genetic and environmental factors are independent of one another.

  • May combine two claims.

    Premisenone given

    Adding nontwin siblings to twin data increases generalizability and improves precision.

    “Although twins are important for etiological studies, also including nontwin siblings provide greater generalizability and simultaneously improve precision.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Small sample size, ascertainment bias, or both could raise estimates of the shared environmental effect.

    “Bias owing to small sample size, ascertainment bias, or both, could lead to elevated estimates of shared environmental effect.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Shared environmental factors in this study may capture variables or processes that make members of the same family alike beyond genetic factors.

    “Shared environmental factors in this study may reflect variables or processes that make members of the same family similar beyond genetic factors.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Using contemporary clinical diagnoses rather than questionnaire-based symptom checklists increases generalizability and helps avoid biases that may be embedded in subclinical diagnoses.

    “Using contemporary clinical diagnoses adds to generalizability and helps to avoid biases that could be embedded in subclinical diagnoses.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    Twin studies rest on specific assumptions about genetic and environmental correlations, and applying different study designs makes results less dependent on those assumptions.

    “Twin studies rely on very specific assumptions about genetic and environmental correlations.Applying different study designs make results less sensitive to these crucial assumptions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    A multigenerational family design was chosen because relatedness determines genetic correlation and permits estimation of additive genetic, maternal, and shared environmental components.

    “We chose a multigenerational family design because the strength of genetically induced correlation for a given trait varies by the degree of relatedness between relatives, which allows additive genetic (heritability), maternal, and shared environmental effects to be estimated.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Marker-based (single-nucleotide polymorphism) approaches currently give only a lower bound for heritability.

    “Although these make a valuable contribution, currently they provide only a lower bound for heritability.35”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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43 of 43

  • The authors state this as an assumption.

    After divorce or separation, children remained with their mothers.

    “an assumption behind this decision is that children lived with their mothers after a divorce and separation from the father, an assumption frequently made in these types of models; this is also the rationale for excluding half siblings in our analytic sample.”

  • The paper relies on this without support.

    The Danish, Finnish, and Swedish health, ascertainment, and diagnostic systems are alike.

    “Because Denmark, Finland, and Sweden share similar health, ascertainment, and diagnostic systems, and because of sample size considerations, the primary pooled analysis focused on the Danish, Finnish, and Swedish samples.”

  • The authors state this as an assumption.

    Genetic and environmental factors are independent of one another.

    “The first potential misspecification arises from the possible violation of the assumption of independence between genetic and environment.”

  • The authors state this as an assumption.

    Ascertainment of ASD in sibling pairs is independent.

    “Any study using differences in ASD occurrence between sibling pairs will rely on the assumption of independent ascertainment.”
4 of 4

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Maternal-effect estimates are cited to a table without maternal effects

    Minor

    The discussion cites Table 3 for maternal-effect estimates, but Table 3 reports only additive genetic, shared-environment, and nonshared-environment effects.

  • Finland's shared-environment estimate is attributed to Denmark

    Minor

    The text attributes the ACE model's 14.5% shared-environment estimate to Denmark, but Table 2 assigns that estimate and confidence interval to Finland. Denmark's estimate in the table is 0.0%.

2 of 2

Cites

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Authors
Bai, D., Yip, B. H. K., Windham, G. C., Sourander, A., Francis, R., Yoffe, R., Glasson, E., Mahjani, B., Suominen, A., Leonard, H., Gissler, M., Buxbaum, J. D., Wong, K., Schendel, D., Kodesh, A., Breshnahan, M., Levine, S. Z., Parner, E. T., Hansen, S. N., Hultman, C., Reichenberg, A., & Sandin, S.
Affiliations
  • Chinese University of Hong Kong (HK)
  • California Department of Public Health (US)
  • Department of Child Psychiatry, Turku University, Turku University Hospital, Turku, Finland
  • The Kids Research Institute Australia (AU)
  • Israel Ministry of Health (IL)
  • Karolinska Institutet (SE)
  • University of Turku (FI)
  • Icahn School of Medicine at Mount Sinai (US)
  • Aarhus University (DK)
  • Kupat Holim Meuchedet (IL)
  • Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York
  • University of Haifa (IL)
Corresponding author
Sandin, Sven
ORCID
Venue
JAMA Psychiatry
Publisher
American Medical Association (AMA)
Published
2019-10-01
Volume
76
Issue
10
Pages
1035
ISSN
2168-622X (ISSN-L)
DOI
10.1001/jamapsychiatry.2019.1411
PMC
PMC6646998
OpenAlex
W2959289532
Semantic Scholar
a623067836e97eeb3fe5e3f5142fcafcdcd00467
Cited by
683
References
43
Citations by year
2026: 128 · 2025: 103 · 2024: 105 · 2023: 72 · 2022: 106 · 2021: 86 · 2020: 70 · 2019: 10 · 2018: 1 · 2014: 1
FWCI
39.50
Type
journal article
Language
en
Open access
Locations
  • JAMA Psychiatry (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
  • STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
Funders
Lundbeckfonden (R248‐2017‐2003)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
autism spectrum disorder, heritability, additive genetic effects, maternal effects, shared environmental effects, variance components, autistic disorder, ASD risk factors, cross-national comparison
MeSH terms
Autism Spectrum Disorder, Maternal Inheritance, Adolescent, Autistic Disorder, Child, Denmark, Environment, Family, Female, Finland, Humans, Israel, Male, Sensitivity and Specificity, Sweden, Western Australia, Cohort Studies, Genetic Predisposition to Disease, Inheritance Patterns, Genetic Association Studies

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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