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- Wang, T, et al.
(författare)
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Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 4932-
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Tidskriftsartikel (refereegranskat)abstract
- Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E−07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.
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- Buitelaar, J, et al.
(författare)
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Toward Precision Medicine in ADHD
- 2022
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Ingår i: Frontiers in behavioral neuroscience. - : Frontiers Media SA. - 1662-5153. ; 16, s. 900981-
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Tidskriftsartikel (refereegranskat)abstract
- Attention-Deficit Hyperactivity Disorder (ADHD) is a complex and heterogeneous neurodevelopmental condition for which curative treatments are lacking. Whilst pharmacological treatments are generally effective and safe, there is considerable inter-individual variability among patients regarding treatment response, required dose, and tolerability. Many of the non-pharmacological treatments, which are preferred to drug-treatment by some patients, either lack efficacy for core symptoms or are associated with small effect sizes. No evidence-based decision tools are currently available to allocate pharmacological or psychosocial treatments based on the patient's clinical, environmental, cognitive, genetic, or biological characteristics. We systematically reviewed potential biomarkers that may help in diagnosing ADHD and/or stratifying ADHD into more homogeneous subgroups and/or predict clinical course, treatment response, and long-term outcome across the lifespan. Most work involved exploratory studies with cognitive, actigraphic and EEG diagnostic markers to predict ADHD, along with relatively few studies exploring markers to subtype ADHD and predict response to treatment. There is a critical need for multisite prospective carefully designed experimentally controlled or observational studies to identify biomarkers that index inter-individual variability and/or predict treatment response.
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- Hibar, Derrek P., et al.
(författare)
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Novel genetic loci associated with hippocampal volume
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r(g) = -0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.
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- Pijl, M. K. J., et al.
(författare)
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Parent-child interaction during the first year of life in infants at elevated likelihood of autism spectrum disorder
- 2021
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Ingår i: Infant Behavior and Development. - : Elsevier. - 0163-6383 .- 1879-0453 .- 1934-8800. ; 62
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Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorder (ASD) likely emerges from a complex interaction between pre-existing neurodevelopmental vulnerabilities and the environment. The interaction with parents forms a key aspect of an infant’s social environment, but few prospective studies of infants at elevated likelihood (EL) for ASD (who have an older sibling with ASD) have examined parent-child interactions in the first year of life. As part of a European multisite network, parent-child dyads of free play were observed at 5 months (62 EL infants, 47 infants at typical likelihood (TL)) and 10 months (101 EL siblings, 77 TL siblings). The newly-developed Parent-Infant/Toddler Coding of Interaction (PInTCI) scheme was used, focusing on global characteristics of infant and parent behaviors. Coders were blind to participant information. Linear mixed model analyses showed no significant group differences in infant or parent behaviors at 5 or 10 months of age (all ps≥0.09, d≤0.36), controlling for infant’s sex and age, and parental educational level. However, without adjustments, EL infants showed fewer and less clear initiations at 10 months than TL infants (p = 0.02, d = 0.44), but statistical significance was lost after controlling for parental education (p = 0.09, d = 0.36), which tended to be lower in the EL group. Consistent with previous literature focusing on parent-infant dyads, our findings suggest that differences between EL and TL dyads may only be subtle during the first year of life. We discuss possible explanations and implications for future developmental studies.
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- Satizabal, Claudia L., et al.
(författare)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Tidskriftsartikel (refereegranskat)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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