Contribution of rare and common variants to intellectual disability in a high-risk population sub-isolate of Northern Finland

Kurki, M.; Saarentaus, Elmo; Pietiläinen, Olli; Gormley, Padhraig; Lal, Dennis; Kerminen, Sini; Holm, Minna; Hämäläinen, Eija; Rahikkala, Elisa; Keski‐Filppula, Riikka; Rauhala, Merja; Korpi-Heikkila, Satu; Komulainen‐Ebrahim, Jonna; Helander, Heli; Vieira, Päivi; Salomaa, Veikko; Pirinen, Matti; Suvisaari, Jaana; Moilanen, JS; Körkkö, Jarmo; Kuismin, Outi; Daly, Mark J.; Palotie, Aarno

doi:10.1101/332023

Cited by 5 publications

(7 citation statements)

References 51 publications

(35 reference statements)

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“…Finland. SCZ showed a higher polygenic risk in EF than in WF, which is in line with extensive geographic incidence information from several studies (Lehtinen et al 1990;Hovatta et al 1997;Haukka et al 2001;Perala et al 2008;Pietiläinen 2014;Kurki et al 2018) that describe highest SCZ prevalence/incidence rates in Northern and Eastern Finland and lowest rates in the Southwestern parts of the country. Also, RA showed higher polygenic risk in EF than in WF.…”

Section: Discussionsupporting

confidence: 84%

Geographic variation and bias in polygenic scores of complex diseases and traits in Finland

Kerminen

Martin

Koskela

et al. 2018

Preprint

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Polygenic scores (PS) are becoming a useful tool to identify individuals with high genetic risk for complex diseases and several projects are currently testing their utility for translational applications.It is also tempting to use PS to assess whether genetic variation can explain a part of the geographic distribution of a phenotype. However, it is not well known how population genetic properties of the training and target samples affect the geographic distribution of PS. Here, we evaluate geographic differences, and related biases, of PS in Finland with geographically well-defined sample of 2,376 individuals from the National FINRISK study. First, we detect geographic differences in PS for coronary artery disease (CAD), rheumatoid arthritis, schizophrenia, waits-hip ratio (WHR), bodymass index (BMI) and height, but not for Crohn's disease or ulcerative colitis. Second, we use height as a model trait to thoroughly assess the possible population genetic biases in PS and apply similar approaches to the other phenotypes. Most importantly, we detect suspiciously large accumulation of geographic differences for CAD, WHR, BMI and height, suggesting bias arising from population genetic structure rather than from a direct genotype-phenotype association. This work demonstrates how sensitive the geographic patterns of current PS are for small biases even within relatively homogenous populations and provides simple tools to identify such biases. A thorough understanding of the effects of population genetic structure on PS is essential for translational applications of PS.

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Section: Discussionsupporting

confidence: 84%

Geographic variation and bias in polygenic scores of complex diseases and traits in Finland

Kerminen

Martin

Koskela

et al. 2018

Preprint

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“…In total, 211 patients with ID of unknown cause were collected from Northeastern Finland for the study. In addition, six cases homozygous for c.509G>A p.(Arg170His) variant from Northern Finland Intellectual Disability (NFID) project [16] and two cases identified directly in the clinic by one of the authors (ER) were included into the detailed phenotype analysis. Finally, two Finnish siblings with pachygyria [17] belong to a collection of cases with prenatal ventriculomegaly and/or congenital, primary hydrocephalus whose genetic background was studied by the group of MA.…”

Section: Methodsmentioning

confidence: 99%

“…Data analysis were performed using the Roche Newbler software (v.2.3) using human genome build hg19/GRCh37. Exome sequencing and targeted Sanger sequencing were also used to analyze the data of 757 patients with ID of unknown etiology belonging to the NFID cohort to identify the CRADD founder variant in six additional cases with pachygyria, see detailed description of the project in Kurki et al [16].…”

Section: Exome Sequencing (Es)mentioning

confidence: 99%

Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant pachygyria in the Finnish population

et al. 2019

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Intellectual disability (ID), megalencephaly, frontal predominant pachygyria, and seizures, previously called "thin" lissencephaly, are reported to be caused by recessive variants in CRADD. Among five families of different ethnicities identified, one homozygous missense variant, c.509G>A p.(Arg170His), was of Finnish ancestry. Here we report on the phenotypic variability associated for this potential CRADD founder variant in 22 Finnish individuals. Exome sequencing was used to identify candidate genes in Finnish patients presenting with ID. Targeted Sanger sequencing and restriction enzyme analysis were applied to screen for the c.509G>A CRADD variant in cohorts from Finland. Detailed phenotyping and genealogical studies were performed. Twenty two patients were identified with the c.509G>A p.(Arg170His) homozygous variant in CRADD. The majority of the ancestors originated from Northeastern Finland indicating a founder effect. The hallmark of the disease is frontotemporal predominant pachygyria with mild cortical thickening. All patients show ID of variable severity. Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients and megalencephaly in three patients. This study provides detailed data about the phenotypic spectrum of patients with lissencephaly due to a CRADD variant that affects function. High inter-and intrafamilial phenotypic heterogeneity was identified in patients with pachygyria caused by the homozygous CRADD founder variant. The phenotype variability suggests that additional genetic and/or environmental factors play a role in the clinical presentation. Since frontotemporal pachygyria is the hallmark of the disease, brain imaging studies are essential to support the molecular diagnosis for individuals with ID and a CRADD variant.

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“…This is consistent with the detrimental effects of ASD on both attainment and measurement of cognitive and adaptive abilities (41, 42). With respect to the severity of ID, the fact that individuals with both ASD and ID are particularly likely to have a specific genetic etiology, and that severe to profound ID is more common in such cases of rare genetic syndromes than in the general ID population (43), results in a theoretical and non-hereditary “bump” in the normal distribution at the very low end of IQ (44).…”

Section: Diagnostic and Statistical Manual Of Mental Disorders (Dsm)mentioning

confidence: 99%

State of the Field: Differentiating Intellectual Disability From Autism Spectrum Disorder

et al. 2019

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The topic of this special issue on secondary versus idiopathic autism allows for discussion of how different groups may come to manifest autism spectrum disorder (ASD) or ASD-like symptoms despite important etiological differences. A related issue is that, because many of the social communication deficits that define ASD represent a failure to acquire developmentally expected skills, these same deficits would be expected to occur to some extent in all individuals with intellectual disability (ID). Thus, regardless of etiology, ASD symptoms may appear across groups of individuals with vastly different profiles of underlying deficits and strengths. In this focused review, we consider the impact of ID on the diagnosis of ASD. We discuss behavioral distinctions between ID and ASD, in light of the diagnostic criterion mandating that ASD should not be diagnosed if symptoms are accounted for by ID or general developmental delay. We review the evolution of the autism diagnosis and ASD diagnostic tools to understand how this distinction has been conceptualized previously. We then consider ways that operationalized criteria may be beneficial for making the clinical distinction between ID with and without ASD. Finally, we consider the impact of the blurred diagnostic boundaries between ID and ASD on the study of secondary versus idiopathic ASD. Especially pertinent to this discussion are findings that a diagnosis of ID in the context of an ASD diagnosis may be one of the strongest indicators that an associated condition or specific etiological factor is present (i.e., secondary autism).

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Contribution of rare and common variants to intellectual disability in a high-risk population sub-isolate of Northern Finland

Cited by 5 publications

References 51 publications

Geographic variation and bias in polygenic scores of complex diseases and traits in Finland

Geographic variation and bias in polygenic scores of complex diseases and traits in Finland

Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant pachygyria in the Finnish population

State of the Field: Differentiating Intellectual Disability From Autism Spectrum Disorder

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