Dataset Information

Distribution and medical impact of loss-of-function variants in the Finnish founder population.

ABSTRACT: Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10??) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P?=?1.5×10?¹¹?). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR?=?0.84, P?=?3×10??), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers.

SUBMITTER: Lim ET

PROVIDER: S-EPMC4117444 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Distribution and medical impact of loss-of-function variants in the Finnish founder population.

Lim Elaine T ET Würtz Peter P Havulinna Aki S AS Palta Priit P Tukiainen Taru T Rehnström Karola K Esko Tõnu T Mägi Reedik R Inouye Michael M Lappalainen Tuuli T Chan Yingleong Y Salem Rany M RM Lek Monkol M Flannick Jason J Sim Xueling X Manning Alisa A Ladenvall Claes C Bumpstead Suzannah S Hämäläinen Eija E Aalto Kristiina K Maksimow Mikael M Salmi Marko M Blankenberg Stefan S Ardissino Diego D Shah Svati S Horne Benjamin B McPherson Ruth R Hovingh Gerald K GK Reilly Muredach P MP Watkins Hugh H Goel Anuj A Farrall Martin M Girelli Domenico D Reiner Alex P AP Stitziel Nathan O NO Kathiresan Sekar S Gabriel Stacey S Barrett Jeffrey C JC Lehtimäki Terho T Laakso Markku M Groop Leif L Kaprio Jaakko J Perola Markus M McCarthy Mark I MI Boehnke Michael M Altshuler David M DM Lindgren Cecilia M CM Hirschhorn Joel N JN Metspalu Andres A Freimer Nelson B NB Zeller Tanja T Jalkanen Sirpa S Koskinen Seppo S Raitakari Olli O Durbin Richard R MacArthur Daniel G DG Salomaa Veikko V Ripatti Samuli S Daly Mark J MJ Palotie Aarno A

PLoS genetics 20140731 7

Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variati ...[more]

PMID: 25078778

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Project description:Biallelic pathogenic variants in SZT2 result in a neurodevelopmental disorder with shared features, including early-onset epilepsy, developmental delay, macrocephaly, and corpus callosum abnormalities. SZT2 is as a critical scaffolding protein in the amino acid sensing arm of the mTORC1 signalling pathway. Due to its large size (3432 amino acids), lack of crystal structure, and absence of functional domains, it is difficult to determine the pathogenicity of SZT2 missense and in-frame deletions, but these variants are increasingly detected and reported by clinical genetic testing in individuals with epilepsy. To exemplify this latter point, here we describe a cohort of 12 individuals with biallelic SZT2 variants and phenotypic overlap with SZT2-related neurodevelopmental disorders. However, the majority of individuals carried one or more SZT2 variants of uncertain significance (VUS), highlighting the need for functional characterization to determine, which, if any, of these VUS were pathogenic. Thus, we developed a novel individualized platform to identify SZT2 loss-of-function variants in the context of mTORC1 signalling and reclassify VUS. Using this platform, we identified a recurrent in-frame deletion (SZT2 p.Val1984del) which was determined to be a loss-of-function variant and therefore likely pathogenic. Haplotype analysis revealed that this single in-frame deletion is a founder variant in those of Ashkenazi Jewish ancestry. Moreover, this approach allowed us to tentatively reclassify all of the VUS in our cohort of 12 individuals, identifying five individuals with biallelic pathogenic or likely pathogenic variants. Clinical features of these five individuals consisted of early-onset seizures (median 24 months), focal seizures, developmental delay and macrocephaly similar to previous reports. However, we also show a widening of the phenotypic spectrum, as none of the five individuals had corpus callosum abnormalities, in contrast to previous reports. Overall, we present a rapid assay to resolve VUS in SZT2, identify a founder variant in individuals of Ashkenazi Jewish ancestry, and demonstrate that corpus callosum abnormalities is not a hallmark feature of this condition. Our approach is widely applicable to other mTORopathies including the most common causes of the focal genetic epilepsies, DEPDC5, TSC1/2, MTOR and NPRL2/3.

Project description:BackgroundHeart rate variability (HRV) and baroreflex sensitivity (BRS) measurements provide means for the objective assessment of cardiovascular autonomic function. As previous studies have associated chronic pain with abnormal autonomic function, we aimed to characterize the relationship between the number of musculoskeletal pain sites (NPS), pain intensity, and cardiovascular autonomic function among the population-based Northern Finland Birth Cohort 1966.MethodsAt the age of 46, cohort members self-reported their musculoskeletal pains (enabling the determination of NPS [0-8] and pain intensity [Numerical Rating Scale, NRS, 0-10]) and underwent clinical assessments of cardiovascular autonomic function in seated and standing positions (HRV variables: heart rate [HR] and root mean square of successive differences in beat-to-beat intervals [rMSSD] for the entire cohort; BRS variables: low-frequency systolic blood pressure variability [SBPV] and cross-spectral baroreflex sensitivity [BRS] for those attending the examination in Oulu, Finland). Extensive confounder data were also collected (body mass index, physical activity, smoking, Hopkins Symptom Checklist-25, comorbidities, and medications). The full samples included 4186 and 2031 individuals (HRV and BRS samples, respectively). Three subanalyses focused on individuals with intense and frequent pain, individuals with symptoms of depression and anxiety, and the relationship between pain intensity and autonomic parameters.ResultsLinear regression models showed varying associations between NPS, pain intensity, and cardiovascular autonomic parameters. However, after all adjustments NPS was only associated with one outcome among women (BRS, standing: beta = - 0.015, p = 0.048) and two among men (HR, seated: beta = - 0.902, p = 0.003; HR, standing: beta = - 0.843, p = 0.014). Pain intensity was not associated with any outcome after full adjustments. Significant sex*pain interactions were found in the data.ConclusionsOur data suggest that musculoskeletal pain has, at most, a limited independent association with cardiovascular autonomic function. Future studies should carefully account for the potential confounders and sex interactions that this study revealed.

Dataset Information

Distribution and medical impact of loss-of-function variants in the Finnish founder population.

Publications

Distribution and medical impact of loss-of-function variants in the Finnish founder population.

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