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Cited by 36Obsessive-Compulsive Spectrum DisordersGenetic Associations and EpidemiologyMaternal Mental Health During Pregnancy and Postpartum

Maternal Effects as Causes of Risk for Obsessive-Compulsive Disorder

Open access
Mahjani, Behrang, Klei, Lambertus, Hultman, Christina M., Larsson, Henrik, Devlin, Bernie, Buxbaum, Joseph D., Sandin, Sven, Grice, Dorothy E.·2020·Biological Psychiatry
DOI 10.1016/j.biopsych.2020.01.006PMC PMC8023336
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Abstract

BACKGROUND: While genetic variation has a known impact on the risk for obsessive-compulsive disorder (OCD), there is also evidence that there are maternal components to this risk. Here, we partitioned sources of variation, including direct genetic and maternal effects, on risk for OCD. METHODS: The study population consisted of 822,843 individuals from the Swedish Medical Birth Register, born in Sweden between January 1, 1982, and December 31, 1990, and followed for a diagnosis of OCD through December 31, 2013. Diagnostic information about OCD was obtained using the Swedish National Patient Register. RESULTS: A total of 7184 individuals in the birth cohort (0.87%) were diagnosed with OCD. After exploring various generalized linear mixed models to fit the diagnostic data, genetic maternal effects accounted for 7.6% (95% credible interval: 6.9%–8.3%) of the total variance in risk for OCD for the best model, and direct additive genetics accounted for 35% (95% credible interval: 32.3%–36.9%). These findings were robust under alternative models. CONCLUSIONS: Our results establish genetic maternal effects as influencing risk for OCD in offspring. We also show that additive genetic effects in OCD are overestimated when maternal effects are not modeled.

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Crossref · 10.1016/j.biopsych.2020.01.006

Cites

54 of 54 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 29 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The model explained 37.8% to 42.6% of the liability of OCD based on direct genetic effects and genetic maternal effects.

    “In total, our model explained 37.8% to 42.6% of the liability of OCD based on DG and GME.”
    Quote in the paperSubstantial claim
  • Findingown data

    The odds ratio for OCD in female versus male individuals was 1.60.

    “We observed an odds ratio of 1.60 for female versus male individuals diagnosed with OCD (Supplemental Table S1).”
    Quote in the paperNot a substantial claim
  • Findingown data

    The population frequency of OCD was higher for children born before 37 weeks of gestation.

    “The population frequency of OCD was higher for gestational age under 37 weeks (Supplemental Tables S12 and S13).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Assortative mating inflated the estimate of direct genetic effects by 4% to 5%.

    “We observed that assortative mating inflated the estimate of DG by 4% to 5% (Supplemental Table S20).”
    Quote in the paperNot a substantial claim
  • Findingown data

    In a model without maternal effects, direct genetic effects accounted for 43.6% to 48.2% of phenotypic variation, compared with 31.9% to 35.0% when maternal effects were included.

    “In a model without maternal effects, 43.6% to 48.2% of the phenotypic variation was estimated as due to direct DG, in contrast to 31.9% to 35.0% if maternal effects were included in the model.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 7
  • May combine two claims. 19

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

    Findingown data

    Among the OCD cases in the cohort, 60% were female.

    “7184 (0.87%) were diagnosed with OCD (60% female) using ICD-10 criteria (Table 1)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The odds ratio for OCD was 2.18 (95% CI 1.96-2.42) in children with maternal psychiatric disorder and 1.88 (95% CI 1.68-2.10) in children with paternal psychiatric disorder.

    “The odds ratio for OCD was 2.18 (95% CI = 1.96–2.42, p = 5.82 × 10−40) or 1.88 (95%CI = 1.68–2.10, p = 2.06 × 10−25) in children with maternal or paternal psychiatric disorder, respectively (Supplemental Tables S6 and S7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The study cohort included 822,843 individuals born in Sweden between 1982 and 1990, and 7,184 of them (0.87%) received an OCD diagnosis.

    “The study population consisted of 822,843 individuals from the Swedish Medical Birth Register, born in Sweden between January 1, 1982, and December 31, 1990, and followed for a diagnosis of OCD through December 31, 2013.”
    • Also stated in: § RESULTS · plain
      “The cohort contains 822,843 individuals, of which 7184 (0.87%) were diagnosed with OCD (60% female) using ICD-10 criteria (Table 1) followed from January 1997 through December 2013.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Liability threshold modeling estimated direct additive genetic effects at 31.9% and genetic maternal effects at 5.8%, similar to the generalized linear mixed model estimates, and provided no evidence for paternal effects.

    “The best LTM estimated DG and GME to be 31.9% and 5.8%, respectively, quite similar to the CrI of the GLMM estimates, and did not provide evidence for paternal effects (Supplemental Table S18).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The odds ratio for OCD in children whose mother had OCD was 4.92 (95% CI 3.92-6.10), and in children whose father had OCD it was 5.11 (95% CI 3.81-6.75).

    “The odds ratio for children having OCD given that either their mother or their father had OCD (using ICD-9) was 4.92 (95% CI = 3.92–6.10, p = 3.93 × 10−32) or 5.11 (95% CI = 3.81–6.75, p = 1.46 × 10−20), respectively (Supplemental Tables S8 and S9).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The maternal and paternal OCD odds ratios were close to each other and to the relative recurrence risk for full siblings (4.82).

    “These estimates are close to one another and with the RRR for full sibs (4.82) (Table 1).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Population frequencies of OCD were 0.0118 for paternal age under 35 and 0.0134 for paternal age over 35, and 0.0120 for maternal age under 35 and 0.0143 for maternal age over 35.

    “For ease of modeling, we created two categories for paternal age: younger than 35 years (population frequency of 0.0118) and older than 35 years (population frequency of 0.0134); we created the same split for maternal age, yielding population frequencies of 0.0120 and 0.0143, respectively (Supplemental Tables S2–S5).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Relative recurrence risk for OCD was higher in maternal half-siblings than in paternal half-siblings, and higher in maternal parallel cousins than in other cousin types.

    “These analyses showed higher point estimates for maternal half-sibs compared with paternal half-sibs as well as higher RRR for maternal cousins compared with other cousins.”
    • Also stated in: § DISCUSSION · plain
      “The RRR for paternal half-sibs was 1.084, while the RRR for maternal half-sibs was 1.849; likewise, maternal parallel cousins carried somewhat higher risk, as compared to other cousins (1.85 vs. 1.595).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The similarity of maternal and paternal OCD odds ratios and the full-sibling relative recurrence risk is consistent with roughly equal direct additive genetic effects on OCD risk from mother and father, and suggests that maternal OCD status is not confounded with maternal effects.

    “This similarity is consistent with roughly equal DG (i.e., additive effects) on OCD risk from both mother and father and suggests that that OCD status of the mother is not confounded with any potential maternal effects on OCD.”
    Quote in the paperSubstantial claim

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

    Study design and conductreasoning

    Ignoring symptom dimensions of OCD and modeling diagnosis as a dichotomous outcome can potentially bias the results.

    “Ignoring the symptom dimensions of OCD and modeling the diagnosis as dichotomous outcomes can potentially bias the results.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The study may not capture individuals diagnosed only as outpatients before 2001, those with milder OCD, or those who did not seek health services.

    “Those who were diagnosed only as outpatients before 2001 or were manifesting milder forms of OCD, or those who did not seek health services, might not be captured in our study design.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Using the complete birth cohort and all family types made exposed and unexposed groups more comparable and minimized selection bias.

    “using the complete birth cohort between 1982 and 1990 and including all different family types, instead of a sample of the population, made the exposed and unexposed groups for different family types more comparable and minimized the selection bias.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    Using the Swedish Medical Birth Register as the sampling frame created a genetically homogeneous sample, minimizing confounding due to population stratification.

    “by using the Swedish Medical Birth Register as our sampling frame, we created a genetically homogeneous sample, minimizing the risk of confounding due to population stratification.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The results strongly favor the model with direct genetic effects and genetic maternal effects, suggesting that shared environmental maternal effects have little or no effect on OCD risk.

    “Our result strongly favors the DG + GME model, suggesting that shared EME have little or no effect on risk.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    The sample is based on clinical diagnoses of OCD by a specialist, which would be expected to reduce biases and case misclassification.

    “our sample is based on clinical diagnoses of OCD by a specialist, which would also be expected to reduce biases and case misclassification.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The data are likely right censored, especially for individuals born in later years, which can contribute to underdiagnosis of OCD and lower the population frequency.

    “In addition, the data are likely right censored, in particular for individuals born in the later years of the study. This can contribute to underdiagnoses of OCD and decreases the population frequency.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The results demonstrate associations between parental factors such as parental age, parental psychiatric history, maternal smoking during pregnancy, and gestational age and risk for OCD.

    “Our results also demonstrate an association between parental factors and risk for OCD such as parental age, parental psychiatric history, maternal smoking during pregnancy, and gestational age, in accordance with previous studies (16).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Brander, 2016, Association of perinatal risk factors with obsessive-compulsive disorder: A population-based birth cohort, sibling control study, JAMA Psychiatry source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Relative recurrence risk estimates were adjusted for sex, maternal and paternal age, maternal and paternal psychiatric history, gestational age, and maternal smoking.

    “We estimated relative recurrence risk (RRR) for all pairs of different relationship types using Cox proportional hazards regression, with attained age as the primary time scale and adjusted for sex, maternal and paternal age, maternal and paternal psychiatric history, gestational age, and maternal smoking.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Assortative mating can impact estimates of heritability, albeit modestly.

    “Assortative mating can impact estimates of heritability, albeit modestly (52);”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Peyrot, 2016, Exploring boundaries for the genetic consequences of assortative mating for psychiatric traits, JAMA Psychiatry source

      Not checked in the free run.

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

    Premisecitation

    Both genetic and environmental factors contribute to the risk of developing OCD.

    “However, both genetic and environmental factors contribute to risk of developing OCD (11–17).”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [11] Browne, 2014, Genetics of obsessive-compulsive disorder and related disorders, Psychiatr Clin North Am source

      Not checked in the free run.

    • cites [12] Nestadt, 2011, Genetics of OCD, Psychiatr Clin North Am

      Not checked in the free run.

    • cites [13] Cappi, 2016, Whole-exome sequencing in obsessive-compulsive disorder identifies rare mutations in immunological and neurodevelopmental pathways, Transl Psychiatry source

      Not checked in the free run.

    • cites [14] Gazzellone, 2016, Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation, J Neurodev Disord source

      Not checked in the free run.

    • cites [15] McGrath, 2014, Copy number variation in obsessive-compulsive disorder and tourette syndrome: A cross-disorder study, J Am Acad Child Adolesc Psychiatry source

      Not checked in the free run.

    • cites [16] Brander, 2016, Association of perinatal risk factors with obsessive-compulsive disorder: A population-based birth cohort, sibling control study, JAMA Psychiatry source

      Not checked in the free run.

    • cites [17] Browne, 2015, Familial clustering of tic disorders and obsessive-compulsive disorder, JAMA Psychiatry source

      Not checked in the free run.

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

    Premisecitation

    The common single nucleotide polymorphism heritability of OCD is estimated at 28% in meta-analyses, while overall heritability is reported at 40% to 50%.

    “The common single nucleotide polymorphism heritability of OCD has been estimated to be 28% in meta-analyses (18), whereas the overall heritability is reported to be 40% to 50% (19–24).”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [18] Arnold, 2018, Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis, Mol Psychiatry source

      Not checked in the free run.

    • cites [19] Clifford, 1984, Genetic and environmental influences on obsessional traits and symptoms, Psychol Med source

      Not checked in the free run.

    • cites [20] Jonnal, 2000, Obsessive and compulsive symptoms in a general population sample of female twins, Am J Med Genet source

      Not checked in the free run.

    • cites [21] Eley, 2003, A twin study of anxiety-related behaviours in pre-school children, J Child Psychol Psychiatry source

      Not checked in the free run.

    • cites [22] Hudziak, 2004, Genetic and environmental contributions to the Child Behavior Checklist Obsessive-Compulsive Scale: A cross-cultural twin study, Arch Gen Psychiatry source

      Not checked in the free run.

    • cites [23] Taylor, 2011, Etiology of obsessions and compulsions: A meta-analysis and narrative review of twin studies, Clin Psychol Rev source

      Not checked in the free run.

    • cites [24] Monzani, 2014, The structure of genetic and environmental risk factors for dimensional representations of DSM-5 obsessive-compulsive spectrum disorders, JAMA Psychiatry source

      Not checked in the free run.

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

    Study design and conductnone given

    A liability threshold model was used as a sensitivity check on the generalized linear mixed models, with the expectation that estimates would be similar.

    “we used an LTM to estimate the variance components and compared the results with the estimates from GLMMs, as described in the Supplement, as a simple check on the more complex GLMMs and with the expectation that the estimates would be similar.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Failure to include maternal effects in heritability models when maternal effects are present can lead to inflated estimates of direct additive genetic effects and an incomplete risk architecture.

    “Failure to include maternal effects in heritability models, when maternal effects are present, can lead to inflated estimates of direct additive genetic effects (36) and the formulation of an incomplete risk architecture.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Devlin, 1997, The heritability of IQ, Nature source

      Not checked in the free run.

23 of 23

  • The authors state this as an assumption.

    The binary OCD outcome is derived from an underlying normally distributed liability trait with a threshold.

    “These models assume that a binary outcome is derived from an underlying normally distributed trait with an observed threshold value.”
    “Using GLMMs, and under the liability threshold assumption, we estimated that 7.6% (95% CrI = 6.9%–8.3%) of the variance in risk is explained by GME and 35% (95% CrI = 32.3%–36.9%) is explained by DG”

  • The authors state this as an assumption.

    Environmental maternal effects are assumed to be zero for paternal half-siblings and cousins.

    “while it is assumed to be zero for paternal half-sibs and cousins (44).”

  • The authors state this as an assumption.

    Genetic maternal effects contribute to full siblings, maternal half-siblings, and maternal parallel cousins, while environmental maternal effects contribute to full siblings and maternal half-siblings.

    “GME contributes to full sibs, maternal half-sibs, and maternal parallel cousins. EME contributes to full sibs and maternal half-sibs, while it is assumed to be zero for paternal half-sibs and cousins (44).”
3 of 3

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.

  • Age-group OCD frequencies exceed the cohort frequency

    Minor

    The reported OCD frequency for the full cohort is 0.87%, but every stated parental-age group has a frequency of at least 1.18%. If the two age groups partition the same cohort, their overall frequency cannot be lower than both group frequencies.

1 of 1

Cites

Flagged first, then by citations

1 of the 55 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Nestadt, 2011, Genetics of OCD, Psychiatr Clin North Am, 33, 1

Cited by

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Related

Authors
Mahjani, B., Klei, L., Hultman, C. M., Larsson, H., Devlin, B., Buxbaum, J. D., Sandin, S., & Grice, D. E.
Affiliations
  • Karolinska Institutet (SE)
  • University of Pittsburgh (US)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Grice, Dorothy E.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2020-06
Volume
87
Issue
12
Pages
1045-1051
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2020.01.006
PMC
PMC8023336
OpenAlex
W3002126350
Semantic Scholar
cb454ad5ba69648317f3e6a32703283eea968f6b
Cited by
36
References
55
Citations by year
2026: 6 · 2025: 9 · 2024: 3 · 2023: 7 · 2022: 4 · 2021: 4 · 2020: 3
FWCI
1.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
Beatrice and Samuel A. Seaver Foundation
Topics
  • Social Sciences › Psychology › Clinical Psychology › Obsessive-Compulsive Spectrum Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Maternal Mental Health During Pregnancy and Postpartum
Keywords
obsessive-compulsive disorder, maternal effects, genetic risk, additive genetic effects, heritability, offspring risk, birth cohort, genetic variance partitioning
MeSH terms
Maternal Inheritance, Family, Humans, Obsessive-Compulsive Disorder, Registries, Sweden

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