ORCID Profile
0000-0002-9268-0423
Current Organisations
Norwegian Institute of Public Health
,
University of Oslo
,
Lovisenberg Diaconal Hospital
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Publisher: Springer Science and Business Media LLC
Date: 02-06-2022
DOI: 10.1038/S41588-022-01072-5
Abstract: The substantial phenotypic heterogeneity in autism limits our understanding of its genetic etiology. To address this gap, here we investigated genetic differences between autistic in iduals ( n max = 12,893) based on core and associated features of autism, co-occurring developmental disabilities and sex. We conducted a comprehensive factor analysis of core autism features in autistic in iduals and identified six factors. Common genetic variants were associated with the core factors, but de novo variants were not. We found that higher autism polygenic scores (PGS) were associated with lower likelihood of co-occurring developmental disabilities in autistic in iduals. Furthermore, in autistic in iduals without co-occurring intellectual disability (ID), autism PGS are overinherited by autistic females compared to males. Finally, we observed higher SNP heritability for autistic males and for autistic in iduals without ID. Deeper phenotypic characterization will be critical in determining how the complex underlying genetics shape cognition, behavior and co-occurring conditions in autism.
Publisher: Cold Spring Harbor Laboratory
Date: 16-05-2020
DOI: 10.1101/2020.05.15.097840
Abstract: Indirect genetic effects from relatives may result in misleading quantifications of heritability, but can also be of interest in their own right. In this paper we propose Trio-GCTA, a model for separating direct and indirect genetic effects when genome-wide single nucleotide polymorphism data have been collected from parent-offspring trios. The model is applicable to phenotypes obtained from any of the family members. We discuss appropriate parameter interpretations and apply the method to four exemplar phenotypes offspring birth weight, offspring temperament, maternal relationship satisfaction, and paternal body-mass index, using real data from the Norwegian Mother, Father and Child Cohort Study (MoBa).
Publisher: Springer Science and Business Media LLC
Date: 03-07-2023
Publisher: Springer Science and Business Media LLC
Date: 02-01-2021
Publisher: Cold Spring Harbor Laboratory
Date: 23-10-2021
DOI: 10.1101/2021.10.13.21261078
Abstract: Obsessive-compulsive disorder (OCD) is a heritable disorder, but no definitive, replicated OCD susceptibility loci have yet been identified by any genome-wide association study (GWAS). Here, we report results from a GWAS in the largest OCD case-control s le (N = 14,140 OCD cases and N = 562,117 controls) to date. We explored the genetic architecture of OCD, including its genetic relationships to other psychiatric and non-psychiatric phenotypes. In the GWAS analysis, we identified one SNP associated with OCD at a genome-wide significant level. Subsequent gene-based analyses identified additional two genes as potentially implicated in OCD pathogenesis. All SNPs combined explained 16% of the heritability of OCD. We show sub-stantial positive genetic correlations between OCD and a range of psychiatric disorders, including anxiety disorders, anorexia nervosa, and major depression. We thus for the first time provide evidence of a genome-wide locus implicated in OCD and strengthen previous literature suggesting a polygenic nature of this disorder.
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.JAAC.2021.11.035
Abstract: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for s le overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. The meta-analysis of overall internalizing symptoms (INT Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood s les will be key in paving the way to future GWAS success.
Publisher: Springer Science and Business Media LLC
Date: 18-03-2023
DOI: 10.1038/S41398-023-02348-Y
Abstract: Parental genes may indirectly influence offspring psychiatric outcomes through the environment that parents create for their children. These indirect genetic effects, also known as genetic nurture, could explain in idual differences in common internalising and externalising psychiatric symptoms during childhood. Advanced statistical genetic methods leverage data from families to estimate the overall contribution of parental genetic nurture effects. This study included up to 10,499 children, 5990 mother–child pairs, and 6,222 father–child pairs from the Norwegian Mother Father and Child Study. Genome-based restricted maximum likelihood (GREML) models were applied using software packages GCTA and M-GCTA to estimate variance in maternally reported depressive, disruptive, and attention-deficit hyperactivity disorder (ADHD) symptoms in 8-year-olds that was explained by direct offspring genetic effects and maternal or paternal genetic nurture. There was no strong evidence of genetic nurture in this s le, although a suggestive paternal genetic nurture effect on offspring depressive symptoms (variance explained (V) = 0.098, standard error (SE) = 0.057) and a suggestive maternal genetic nurture effect on ADHD symptoms (V = 0.084, SE = 0.058) was observed. The results indicate that parental genetic nurture effects could be of some relevance in explaining in idual differences in childhood psychiatric symptoms. However, robustly estimating their contribution is a challenge for researchers given the current paucity of large-scale s les of genotyped families with information on childhood psychiatric outcomes.
Publisher: Springer Science and Business Media LLC
Date: 10-06-2023
DOI: 10.1038/S41467-023-38951-2
Abstract: Genotypes causing pregnancy loss and perinatal mortality are depleted among living in iduals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million in iduals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.
Publisher: Springer Science and Business Media LLC
Date: 14-07-2020
DOI: 10.1038/S41467-020-17117-4
Abstract: Estimates from Mendelian randomization studies of unrelated in iduals can be biased due to uncontrolled confounding from familial effects. Here we describe methods for within-family Mendelian randomization analyses and use simulation studies to show that family-based analyses can reduce such biases. We illustrate empirically how familial effects can affect estimates using data from 61,008 siblings from the Nord-Trøndelag Health Study and UK Biobank and replicated our findings using 222,368 siblings from 23andMe. Both Mendelian randomization estimates using unrelated in iduals and within family methods reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while Mendelian randomization estimates from s les of unrelated in iduals suggested that taller height and lower BMI increase educational attainment, these effects were strongly attenuated in within-family Mendelian randomization analyses. Our findings indicate the necessity of controlling for population structure and familial effects in Mendelian randomization studies.
Publisher: Springer Science and Business Media LLC
Date: 30-07-2021
DOI: 10.1038/S41398-021-01480-X
Abstract: Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for s le overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGG overall ) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG overall . The gene-based analysis returned three significant genes: ST3GAL3 ( P = 1.6E–06), PCDH7 ( P = 2.0E–06), and IPO13 ( P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout s le of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations ( r g ) among rater-specific assessment of AGG ranged from r g = 0.46 between self- and teacher-assessment to r g = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong r g s with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range $$\left| {r_g} \right|$$ r g : 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation ( r g = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range $$\left| {r_g} \right|$$ r g : 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
Publisher: Cold Spring Harbor Laboratory
Date: 09-04-2019
DOI: 10.1101/602516
Abstract: Mendelian randomization (MR) is a widely-used method for causal inference using genetic data. Mendelian randomization studies of unrelated in iduals may be susceptible to bias from family structure, for ex le, through dynastic effects which occur when parental genotypes directly affect offspring phenotypes. Here we describe methods for within-family Mendelian randomization and through simulations show that family-based methods can overcome bias due to dynastic effects. We illustrate these issues empirically using data from 61,008 siblings from the UK Biobank and Nord-Trøndelag Health Study. Both within-family and population-based Mendelian randomization analyses reproduced established effects of lower BMI reducing risk of diabetes and high blood pressure. However, while MR estimates from population-based s les of unrelated in iduals suggested that taller height and lower BMI increase educational attainment, these effects largely disappeared in within-family MR analyses. We found differences between population-based and within-family based estimates, indicating the importance of controlling for family effects and population structure in Mendelian randomization studies.
Publisher: American Medical Association (AMA)
Date: 07-2020
Location: United States of America
No related grants have been discovered for Alexandra Havdahl.