Sweden: Intellectual disability was substantially heritable with 93pct–98pct of the variance in liability attributed to genetic influences

Familial risk and heritability of intellectual disability: a population-based cohort study in Sweden. Paul Lichtenstein et al. Journal of Child Psychology and Psychiatry, December 18 2021 https://doi.org/10.1111/jcpp.13560

Abstract

Background: Intellectual disability (ID) aggregates in families, but factors affecting individual risk and heritability estimates remain unknown.

Methods: A population-based family cohort study of 4,165,785 individuals born 1973–2013 in Sweden, including 37,787 ID individuals and their relatives. The relative risks (RR) of ID with 95% confidence intervals (95% CI) were obtained from stratified Cox proportional-hazards models. Relatives of ID individuals were compared to relatives of unaffected individuals. Structural equation modeling was used to estimate heritability.

Results: Relatives of ID individuals were at increased risk of ID compared to individuals with unaffected relatives. The RR of ID among relatives increased proportionally to the degree of genetic relatedness with ID probands; 256.70(95% CI 161.30–408.53) for monozygotic twins, 16.47(13.32–20.38) for parents, 14.88(12.19–18.16) for children, 7.04(4.67–10.61) for dizygotic twins, 8.38(7.97–8.83) for full siblings, 4.56(4.02–5.16) for maternal, 2.90(2.49–3.37) for paternal half-siblings, 3.03(2.61–3.50) for nephews/nieces, 2.84(2.45–3.29) for uncles/aunts, and 2.04(1.91–2.20) for cousins. Lower RRs were observed for siblings of probands with chromosomal abnormalities (RR 5.53, 4.74–6.46) and more severe ID (mild RR 9.15, 8.55–9.78, moderate RR 8.13, 7.28–9.08, severe RR 6.80, 5.74–8.07, and profound RR 5.88, 4.52–7.65). Male sex of relative and maternal line of relationship with proband was related to higher risk (RR 1.33, 1.25–1.41 for brothers vs. sisters and RR 1.49, 1.34–1.68 for maternal vs. paternal half-siblings). ID was substantially heritable with 0.95(95% CI 0.93–0.98) of the variance in liability attributed to genetic influences.

Conclusions: The risk estimates will benefit researchers, clinicians, families in understanding the risk of ID in the family and the whole population. The higher risk of ID related to male sex and maternal linage will be of value for planning and interpreting etiological studies in ID.

Discussion

Main findings

In this nationwide population-based study, we evaluated familial risk and heritability of ID. The sample of ID probands is 100 times bigger compared to the largest previous study on risk among siblings from British Columbia (Herbst & Baird, 1982). The use of several types of relatives allows evaluating the importance of genetic and environmental risk factors in the etiology of ID.

There are four main findings from our investigation. First, our 20-years risk and frequency of ID in full-siblings are comparable to old reports (Angeli & Kirman, 1975; Becker et al., 1977; Bundey & Carter, 1974; Bundey et al., 1989; Costeff & Weller, 1987; Durkin et al., 1976; Herbst & Baird, 1982; Laxova, Ridler, Bowen-Bravery, & Opitz, 1977; Turner et al., 1971; Turner & Partington, 2000). Now, we provide estimates with narrow confidence intervals also for halfsiblings and other relatives. Moreover, our study is first to report RR for ID comparing relatives of ID probands with relatives of unaffected individuals. High RR for monozygotic twins reflects ID characteristics with 0.9% prevalence and high heritability. Similar RR were reported for autism (Sandin et al., 2014), a disability with similar prevalence (1%–2%) and high (85%) heritability (Sandin et al., 2017).

Second, similar to the study by Bundey et al. (1989), we found no evidence for differences in familial risks related to comorbid medical conditions and adverse birth events, two probable biological mechanisms of ID. It is possible, that some of the birth complications traditionally considered as environmental risk factors reflect the response to genetic abnormalities in the fetus (Bolton et al., 1994; Simonoff, Bolton, & Rutter, 1996).

Third, our findings of an inverse relation between ID severity and the familial risk estimates are in accordance with older studies on siblings (Angeli & Kirman, 1975; Bundey & Carter, 1974; Durkin et al., 1976). We have observed a similar pattern of inheritance in second-degree relatives. A previous study by Reichenberg et al. (2016) showed a normal distribution of intellectual abilities among military conscripts who had siblings with severe ID. But those results are limited by the fact that individuals with medical diagnosis of ID are exempted from military assessment in Sweden and were not likely to be covered by the study. Our results showed a gradual risk decline in relation to level of intellectual impairment with shared etiological links across different levels of severity suggesting that the arbitrary cut-off for classifying ID severity into binary measure seems to be an oversimplification.

Forth, our data provide compelling evidence for the role of sex in familial risk of ID. In our study, we not only confirmed the higher risk for males compared to females in siblings of ID probands, but we also showed that similar sex differences were present in more distant relatives (Table S10). Higher prevalence of ID among males in comparison to females has been reported in population studies (Maulik et al., 2011) but studies in relatives produced ambiguous results, probably due to small sample size (Table S1). Our study confirms that, the sex differences observed in the general population are present in the relatives of ID probands, with males being more predisposed to ID. Matrilineallity was related to a higher risk in half-siblings and cousins of ID individuals in accordance with X-linked ID inheritance pattern.

Previous quantitative genetic methods focused on heritability of general (Kovas et al., 2013; Plomin & Deary, 2015) or low cognitive abilities within the normal range (Reichenberg et al., 2016). Heritability of ID as medical diagnosis has not been estimated before. The concordance in our study was as high as 73% for monozygotic, but relatively low of 9% for dizygotic twins. However, concordance is a measure on an absolute scale and depends on the disease prevalence in the population (Tenesa & Haley, 2013). With ID prevalence of 0.9%, genetic liability may be more accurately measured on a transformed scale by tetrachoric correlations where the liability for a disease is assumed to follow a standard normal distribution. The threshold on the liability distribution is estimated from the observed prevalence of the disease. Individuals are assumed to have a disease if they are above this threshold.

Further, severe ID is often linked to distinct genetic etiology caused by de novo mutations rather than polygenic traits associated with mild ID. In our study, tetrachoric correlations calculated separately for all ID levels and after exclusion of individuals with severe ID resulted in almost identical estimates, suggesting a low contribution of those phenotypes in ID heritability at the population level.

Heritability of ID was estimated to be 95%, considerably higher than 66%–86% reported for cognitive abilities in adulthood (Haworth et al., 2010; Panizzon et al., 2014). Those findings further highlighting importance of familial factors in diagnostics and etiological studies on ID. For future studies on the heritability of ID It is important to consider ‘maternal-effects in etiology’, previously described in quantitative genetic studies on general cognitive abilities (Devlin, Daniels, & Roeder, 1997). Substantially higher RR and 20-years risk estimates for maternal compared with paternal half-siblings were found in our study, suggesting that maternal factors may play an essential role also in clinically diagnosed ID.

Strengths and limitations

This study has several strengths, including the sample size, nationwide coverage, and access to both health and educational records. The ID prevalence of 0.9% in our study is close to 1% provided by the meta-analysis (Maulik et al., 2011). Swedish pediatric healthcare is publically funded with universal access to both primary and nonprimary healthcare (Wettergren, Blennow, Hjern, Soder, & Ludvigsson, 2016). A large number of relatives of ID probands allowed us to provide precise estimates of familial risk for several types of kinship. The RRs in this article are the first estimated for ID using a reference from the general population. We do however acknowledge some limitations. First, our study focused only on Swedish born individuals, not including immigrants. Second, despite the universal access to health care we cannot eliminate the possibility that socially disadvantaged groups such as individuals with substance misuse, experiencing homelessness or involved with justice system, could be less likely to seek psychiatric care and ID can remain underdiagnosed. Also, differences in behavioral manifestation and comorbid disorders between females and males with ID may diminish the likelihood of diagnosing ID in females.

Third, data retrieved from registers are subject to left-censoring with missing data prior to data collection. In our study, the actual time point for ID diagnosis might be earlier then the first record of ID diagnosis. For example, HURPID provides information on the date of graduation from upper secondary schools for pupils with ID (typically after the age of 18 year), not the genuine date of ID diagnosis. Similarly, the precise date of diagnosis is not available for ID individuals diagnosed in outpatient care prior to 2001, when those data has been included in NPR. Those factors can lead to either over-or underestimation of familial risk. Some bias towards higher risk estimates may be present due to assortative mating described for cognitive abilities (Plomin & Deary, 2015).

Conclusions and clinical implications

The findings are of value for planning and interpreting etiological studies in ID. This study provided strong evidence on the familial etiology of ID, mostly related to genetic factors. Precise and up-to-date risk estimates provided by this study will benefit clinicians and families in understanding the risk of ID in the family and the whole population. The significant familial loading in ID suggests that the vulnerabilities of family members should be taken into account in intervention programs in ID.