Familial risk and heritability of intellectual disability: a population‐based cohort study in Sweden

Lichtenstein, Paul; Tideman, Magnus; Sullivan, Patrick F.; Serlachius, Eva; Larsson, Henrik; Kuja‐Halkola, Ralf; Butwicka, Agnieszka

doi:10.1111/jcpp.13560

Cited by 18 publications

(13 citation statements)

References 42 publications

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“…Patients with more severe ID and monogenic disease-associated features in our cohort are then more likely to have a rare, damaging dominant variant than mild ID patients, but there is still a burden of these rare, damaging variants in mild ID patients compared to normal IQ individuals. This burden of rare variation in mild ID patients may appear to be counterintuitive considering the evidence that factors influencing mild ID are similar to those influencing normal cognitive functioning, but recent work has shown that rare, damaging variants contribute to reduced cognitive functioning among even normal IQ individuals [ 3 , 4 ]. We therefore suggest that exome sequencing, including the analysis of potential rare damaging variants, should also be considered as a first-tier diagnostic test for patients with mild ID.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, mild intellectual disability has been characterized as the low extreme of the general population distribution of intelligence, with evidence that factors influencing mild ID are similar to those influencing normal cognitive functioning and that mild ID is qualitatively distinct from severe intellectual disability [ 3 , 4 ]. One assumption is that common genetic variants contribute to the more common diagnosis of mild intellectual disability, while more rare and penetrant variants are the cause of severe and profound ID.…”

Section: Introductionmentioning

confidence: 99%

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Evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability

Urpa,

Kurki,

Rahikkala

et al. 2024

Eur J Hum Genet

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Intellectual disability (ID) is a common disorder, yet there is a wide spectrum of impairment from mild to profoundly affected individuals. Mild ID is seen as the low extreme of the general distribution of intelligence, while severe ID is often seen as a monogenic disorder caused by rare, pathogenic, highly penetrant variants. To investigate the genetic factors influencing mild and severe ID, we evaluated rare and common variation in the Northern Finland Intellectual Disability cohort (n = 1096 ID patients), a cohort with a high percentage of mild ID (n = 550) and from a population bottleneck enriched in rare, damaging variation. Despite this enrichment, we found only a small percentage of ID was due to recessive Finnish-enriched variants (0.5%). A larger proportion was linked to dominant variation, with a significant burden of rare, damaging variation in both mild and severe ID. This rare variant burden was enriched in more severe ID (p = 2.4e-4), patients without a relative with ID (p = 4.76e-4), and in those with features associated with monogenic disorders. We also found a significant burden of common variants associated with decreased cognitive function, with no difference between mild and more severe ID. When we included common and rare variants in a joint model, the rare and common variants had additive effects in both mild and severe ID. A multimodel inference approach also found that common and rare variants together best explained ID status (ΔAIC = 16.8, ΔBIC = 10.2). Overall, we report evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability

Urpa,

Kurki,

Rahikkala

et al. 2024

Eur J Hum Genet

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“…Furthermore, the QR coe cient of the migrant population increases PoD_limb in the 40th to 60th quantile, primarily in rural areas, corroborating ndings that high PoD_limb rates were partly attributable to industrial accidents and other injuries resulting from informal employment(Qiu et al, 2022).Regarding PoD_intellectual, QR results suggest that educational facilities reduce prevalence in the 80th and 90th quantiles, predominantly in rural areas. This implies that enhancing education levels in rural regions could improve medical knowledge (e.g., prenatal care), thereby reducing heredity-related intellectual disabilities(Lichtenstein et al, 2022). Moreover, both OLS and QR results indicate that road density decreases PoD_intellectual, highlighting the importance of road tra c development in rehabilitating intellectual disabilities.…”

mentioning

confidence: 94%

Identifying Urban-Rural Disparities and Dominant Determinants of Prevalence of Disabilities in Tianjin, China

Jiang

Qiu

et al. 2023

Preprint

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In the current context of aging and urbanization, the rapid increase in the prevalence of disabilities (PoDs) has become an important consideration in healthy urban planning. Previous studies have focused on the spatial prevalence of total disabilities based on large-scale survey data. However, few studies have examined different types of PoDs and the factors contributing to spatial disparities in micro-urban units at the municipal level. This study aims to fill this gap by exploring the spatial PoDs, related built environments, and socio-economic factors across Tianjin municipality in 2020. The study employed Getis-Ord GI* analysis to identify urban-rural disparities and OLS and quantile regression analyses to model the heterogeneous effects of the spatial PoDs determinants across quantiles. The results reveal that the PoDs, especially visual, hearing, and limb disabilities, in the urban centre, are significantly higher than those in rural areas, which is inconsistent with previous studies conducted in China. Urbanization rate, medical facilities, and education facilities significantly reduced total PoDs, while the elderly population, migrant population, bus route density, and road density significantly increased it. The built environments and socio-economic factors had heterogeneous impacts on different types of PoDs, which were summarized into three categories based on the dominant determinants: (1) visual and hearing disabilities were medical facility dominated; (2) intellectual and limb disabilities were urbanization, and aging dominated; and (3) mental and speech disabilities were migrant dominated. This study provides scientific advice to adapt to the expected increase in demand for disability-related medical and public health services and to expand the range of effective strategies and interventions aimed at preventing the deterioration of disability and improving disability management in the population.

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“…The paper by Lichtenstein et al. in this issue is certain to become a classic in research on intellectual disability (ID) (Lichtenstein et al., 2022). The sampling frame is the total Swedish population of over four million people with links to health and education registers.…”

Section: Introductionmentioning

confidence: 99%

Commentary: The origins of intellectual disability

Plomin

2022

Child Psychology Psychiatry

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Despite the importance and prevalence of intellectual disability (ID), its origins have not been well understood until now. Lichtenstein et al. report in this issue findings from a population‐based sample four times larger than all previous family studies of ID put together (Lichtenstein et al., 2022). From more than four million people, 37,787 individuals were identified with ID. Relative risks (RRs) are reported for relatives of ID probands (55,000 first‐degree, 55,000 second‐degree, and 170,000 third‐degree) as compared with matched relatives of individuals without ID. These relatives plus 400 pairs of twins in which at least one twin was diagnosed with ID yield an astonishing estimate of 95% heritability with no evidence for shared environmental influence in their model. Another important finding is that maternal half‐siblings of ID individuals were at greater risk than paternal half‐siblings, a maternal effect that could indicate X‐chromosome linkage. Finally, profound and severe ID is etiologically distinct from the normal distribution, due in part to noninherited (de novo) genetic mutations and chromosomal abnormalities. However, 90% of individuals with ID are moderate or mild, and these represent the low end of the normal distribution of genetic influence on cognitive ability, which has important implications for DNA research on ID.

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Familial risk and heritability of intellectual disability: a population‐based cohort study in Sweden

Cited by 18 publications

References 42 publications

Evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability

Evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability

Identifying Urban-Rural Disparities and Dominant Determinants of Prevalence of Disabilities in Tianjin, China

Commentary: The origins of intellectual disability

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