Risk of Psychiatric Disorders Among Individuals With the 22q11.2 Deletion or Duplication

Hoeffding, Louise K.; Trabjerg, Betina B.; Olsen, Line; Mazin, Wiktor; Sparsø, Thomas; Vangkilde, Anders; Mortensen, Preben Bo; Pedersen, Carsten Bøcker; Werge, Thomas

doi:10.1001/jamapsychiatry.2016.3939

Cited by 95 publications

(87 citation statements)

References 51 publications

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“…Such variation may emerge from interacting environmental influences (see below) and/or interactions with variable elements of family genetic background, as observed in 22q11.2 and 16p11.2 deletion syndromes [69,70]. The concept of pleiotropy also applies to heritable behavioral expressions of multiple dimensions of psychopathology, including liability to internalizing disorders, externalizing disorders, and psychotic disorders [71,72].…”

Section: Developmental Psychopathology and Psychiatry: Selected Tenetmentioning

confidence: 99%

Psychiatry and developmental psychopathology: Unifying themes and future directions

Beauchaine

Constantino²,

Hayden

2018

Comprehensive Psychiatry

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In the past 35 years, developmental psychopathology has grown into a flourishing discipline that shares a scientific agenda with contemporary psychiatry. In this editorial, which introduces the special issue, we describe the history of developmental psychopathology, including core principles that bridge allied disciplines. These include (1) emphasis on interdisciplinary research, (2) elucidation of multicausal pathways to seemingly single disorders (phenocopies), (3) description of divergent multifinal outcomes from common etiological start points (pathoplasticity), and (4) research conducted across multiple levels of analysis spanning genes to environments. Next, we discuss neurodevelopmental models of psychopathology, and provide selected examples. We emphasize differential neuromaturation of subcortical and cortical neural networks and connectivity, and how both acute and protracted environmental insults can compromise neural structure and function. To date, developmental psychopathology has placed greater emphasis than psychiatry on neuromaturational models of mental illness. However, this gap is closing rapidly as advances in technology render etiopathophysiologies of psychopathology more interrogable. We end with suggestions for future interdisciplinary research, including the need to evaluate measurement invariance across development, and to construct more valid assessment methods where indicated.

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Section: Developmental Psychopathology and Psychiatry: Selected Tenetmentioning

confidence: 99%

Psychiatry and developmental psychopathology: Unifying themes and future directions

Beauchaine

Constantino²,

Hayden

2018

Comprehensive Psychiatry

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“…While evidence supports a strong genetic influence on its etiology, the precise mechanisms through which genetic variation causally results in ASD are still poorly understood. Hemizygous deletion at human 22q11.2 is one of the rare copy number variants that are robustly associated with ASD (Niklasson et al, 2002;Fine et al, 2005;Antshel et al, 2007;Kates et al, 2007;Schneider et al, 2014;Hoeffding et al, 2017;Zinkstok et al, 2019). TBX1 is one of the genes encoded in 22q11.2 and several cases of TBX1 mutations are associated with ASD (Gong et al, 2001;Ogata et al, 2014;Paylor et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Maternal approach behaviors toward neonatal calls are impaired by mother’s experiences of raising pups with a risk gene variant for autism

Kato

Machida

Nomoto

et al. 2020

Preprint

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How the intrinsic sequence structure of neonatal mouse pup ultrasonic vocalization (USV) and maternal experiences determine maternal behaviors in mice is poorly understood. Our previous work showed that pups with a Tbx1 heterozygous (HT) mutation, a genetic risk for autism spectrum disorder (ASD), emit altered call sequences that do not induce maternal approach behaviors in C57BL6/J mothers. Here, we tested how maternal approach behaviors induced by wild-type and HT USVs are influenced by the mother's experience in raising pups of these two genotypes. The results showed that wild-type USVs were effective in inducing maternal approach behaviors when mothers raised wild-type but not HT pups. The USVs of HT pups were ineffective regardless of whether mothers raised HT or wild-type pups. However, the sequence structure of pup USVs had no effect on the general, non-directional incentive motivation of maternal behaviors. Our data show how the mother's experience with a pup with a genetic risk for ASD alters the intrinsic incentive values of USV sequences in maternal approach behaviors.

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“…Gene dosage cannot be experimentally manipulated in humans as it can in animal or in vitro models, but a similar framework emerges via naturally occurring genetic variation. Such genomic imbalances confer some of the highest genetic risk factors for prevalent developmental neuropsychiatric disorders (Malhotra and Sebat, 2012;Hoeffding et al, 2017) and offer a quasi-experimental "reverse genetics" approach to elucidate how genes may impact neurodevelopmental phenotypes (Hiroi et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Mapping 22q11.2 Gene Dosage Effects on Brain Morphometry

et al. 2017

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Reciprocal chromosomal rearrangements at the 22q11.2 locus are associated with elevated risk of neurodevelopmental disorders. The 22q11.2 deletion confers the highest known genetic risk for schizophrenia, but a duplication in the same region is strongly associated with autism and is less common in schizophrenia cases than in the general population. Here we conducted the first study of 22q11.2 gene dosage effects on brain structure in a sample of 143 human subjects: 66 with 22q11.2 deletions (22q-del; 32 males), 21 with 22q11.2 duplications (22q-dup; 14 males), and 56 age-and sex-matched controls (31 males). 22q11.2 gene dosage varied positively with intracranial volume, gray and white matter volume, and cortical surface area (deletion Ͻ control Ͻ duplication). In contrast, gene dosage varied negatively with mean cortical thickness (deletion Ͼ control Ͼ duplication). Widespread differences were observed for cortical surface area with more localized effects on cortical thickness. These diametric patterns extended into subcortical regions: 22q-dup carriers had a significantly larger right hippocampus, on average, but lower right caudate and corpus callosum volume, relative to 22q-del carriers. Novel subcortical shape analysis revealed greater radial distance (thickness) of the right amygdala and left thalamus, and localized increases and decreases in subregions of the caudate, putamen, and hippocampus in 22q-dup relative to 22q-del carriers. This study provides the first evidence that 22q11.2 is a genomic region associated with gene-dose-dependent brain phenotypes. Pervasive effects on cortical surface area imply that this copy number variant affects brain structure early in the course of development.

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Risk of Psychiatric Disorders Among Individuals With the 22q11.2 Deletion or Duplication

Cited by 95 publications

References 51 publications

Psychiatry and developmental psychopathology: Unifying themes and future directions

Psychiatry and developmental psychopathology: Unifying themes and future directions

Maternal approach behaviors toward neonatal calls are impaired by mother’s experiences of raising pups with a risk gene variant for autism

Mapping 22q11.2 Gene Dosage Effects on Brain Morphometry

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