25 research outputs found
Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia
Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (ÎČ = â0.71 to â1.37; P \u3c 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (ÎČ = â0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P=0.0032, 8.9 Ă 10â6, 1.7 Ă 10â9, 3.5 Ă 10â12 and 1.0 Ă 10â4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to noncarriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes
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Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.
Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (ÎČâ=â-0.71 to -1.37; Pâ<â0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (ÎČâ=â-0.95, Pâ=â0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (Pâ=â0.0032, 8.9âĂâ10-6, 1.7âĂâ10-9, 3.5âĂâ10-12 and 1.0âĂâ10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes
Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder
Publisher's version (Ăștgefin grein).Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable common childhood-onset neurodevelopmental disorder. Some rare copy number variations (CNVs) affect multiple neurodevelopmental disorders such as intellectual disability, autism spectrum disorders (ASD), schizophrenia and ADHD. The aim of this study is to determine to what extent ADHD shares high risk CNV alleles with schizophrenia and ASD. We compiled 19 neuropsychiatric CNVs and test 14, with sufficient power, for association with ADHD in Icelandic and Norwegian samples. Eight associate with ADHD; deletions at 2p16.3 (NRXN1), 15q11.2, 15q13.3 (BP4 & BP4.5âBP5) and 22q11.21, and duplications at 1q21.1 distal, 16p11.2 proximal, 16p13.11 and 22q11.21. Six of the CNVs have not been associated with ADHD before. As a group, the 19 CNVs associate with ADHD (OR = 2.43, P = 1.6 Ă 10â21), even when comorbid ASD and schizophrenia are excluded from the sample. These results highlight the pleiotropic effect of the neuropsychiatric CNVs and add evidence for ADHD, ASD and schizophrenia being related neurodevelopmental disorders rather than distinct entities.We are grateful to the participants and we thank the staff at the Research
Recruitment Center. We also thank the staff at deCODE genetics core facilities
and all our colleagues for their important contribution to this work. We are
grateful to the Benefit Society for Children with Disabilities (Styrktarfélag
LamaĂ°ra og FatlaĂ°ra; SLF) for their participation. The research leading to these
results has received support from the Innovative Medicines Initiative Joint
Undertaking under grant agreementsâ no. 115008 (NEWMEDS) and no. 115300
(EUAIMS), of which resources are composed of EFPIA in-kind contribution and
financial contribution from the European Unionâs Seventh Framework
Programme (EU-FP7/2007â2013), from EU-FP7 grants no. 602450
(IMAGEMEND) and no. 502805 (Aggressotype), EU-FP7-People-2011-IAPP grant
no. 286213 (PsychDPC), and The Research Council of Norway (#226971,
229129, 223273, 213694, 248778), the KG Jebsen Stiftelsen (SKGJ-MED-002 and
SKGJ-MED-008), and The South-East Norway Health Authority (#2012â132).Peer Reviewe
MAP1B mutations cause intellectual disability and extensive white matter deficit
Publisher's version (Ăștgefin grein).
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.Discovery of coding variants in genes that confer risk of neurodevelopmental disorders is an
important step towards understanding the pathophysiology of these disorders. Wholegenome sequencing of 31,463 Icelanders uncovers a frameshift variant (E712KfsTer10) in
microtubule-associated protein 1B (MAP1B) that associates with ID/low IQ in a large pedigree
(genome-wide corrected P = 0.022). Additional stop-gain variants in MAP1B (E1032Ter and
R1664Ter) validate the association with ID and IQ. Carriers have 24% less white matter
(WM) volume (ÎČ = â2.1SD, P = 5.1 Ă 10â8), 47% less corpus callosum (CC) volume (ÎČ =
â2.4SD, P = 5.5 Ă 10â10) and lower brain-wide fractional anisotropy (P = 6.7 Ă 10â4). In
summary, we show that loss of MAP1B function affects general cognitive ability through a
profound, brain-wide WM deficit with likely disordered or compromised axons.We are grateful to the participants and we thank the psychologists, nurses and staff, in
particular Berglind Eiriksdottir, at the Research Recruitment Center and technicians and
staff at Röntgen Domus. We also thank the staff at deCODE genetics core facilities and
all our colleagues for their important contribution to this work. L.J. received support
from the Swedish Society of Medicine, the Swedish Brain Foundation and Swedish
Society for Medical Research. The research leading to these results has received support
from the Innovative Medicines Initiative Joint Undertaking under grant agreementsâ no.
115008 (NEWMEDS) and no. 115300 (EUAIMS) of which resources are composed of
EFPIA in-kind contribution and financial contribution from the European Unionâs
Seventh Framework Programme (EU-FP7/2007-2013), EU-FP7 funded grant no. 602450
(IMAGEMEND) and EU funded FP7-People-2011-IAPP grant agreement no. 286213
(PsychDPC).Peer Reviewe
Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia
Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (ÎČâ=ââ0.71 to â1.37; Pâ<â0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (ÎČâ=ââ0.95, Pâ=â0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (Pâ=â0.0032, 8.9âĂâ10â6, 1.7âĂâ10â9, 3.5âĂâ10â12 and 1.0âĂâ10â4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes