The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity

Abstract

Anatomical structures and mechanisms linking genes to neuropsychiatric disorders are not deciphered. Reciprocal copy number variants at the 16p11.2 BP4-BP5 locus offer a unique opportunity to study the intermediate phenotypes in carriers at high risk for autism spectrum disorder (ASD) or schizophrenia (SZ). We investigated the variation in brain anatomy in 16p11.2 deletion and duplication carriers. Beyond gene dosage effects on global brain metrics, we show that the number of genomic copies negatively correlated to the gray matter volume and white matter tissue properties in cortico-subcortical regions implicated in reward, language and social cognition. Despite the near absence of ASD or SZ diagnoses in our 16p11.2 cohort, the pattern of brain anatomy changes in carriers spatially overlaps with the well-established structural abnormalities in ASD and SZ. Using measures of peripheral mRNA levels, we confirm our genomic copy number findings. This combined molecular, neuroimaging and clinical approach, applied to larger datasets, will help interpret the relative contributions of genes to neuropsychiatric conditions by measuring their effect on local brain anatomy.

The 16p11.2 Deletion Mouse Model of Autism Exhibits Altered Cortical Progenitor Proliferation and Brain Cytoarchitecture Linked to the ERK MAPK Pathway

“…The 16p11.2 locus contains 27 genes, including the ERK1 gene (MAPK3) and the Major Vault Protein (MVP) gene. MVP is postulated to act as an ERK scaffold that modulates ERK signaling (Kolli, 2004;Liang et al, 2010). We previously detected ASD-related phenotypes in mice lacking ERK1/2 (Selcher et al, 2001;Pucilowska et al, 2012).…”

“…Recurrent copy number variations (CNVs) are genetically linked to neuropsychiatric disorders, autism, and schizophrenia (Levy et al, 2011;Sanders et al, 2011). 16p11.2 chromosomal deletions provide one of the most common genetic linkages to autism, whereas duplications are linked to schizophrenia (Kumar et al, 2008;Weiss et al, 2008;McCarthy et al, 2009;Fernandez et al, 2010).…”

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

“…[2][3][4][5]9,10 The two CNVs have also been shown to interact at the chromatin level, by 4C, FISH, Hi-C, and concomitant expression changes. 17,45 To investigate whether the two regions are also conducive to genetic interactions, we co-injected LAT, the driver of the HC phenotype of the BP2-BP3 CNVs, with mRNAs encoding KCTD13, the driver of the HC phenotype of the BP4-BP5 CNVs, and MAPK3 or MVP, modifiers of the same BP4-BP5 HC phenotype, and we evaluated the number of proliferating cells.…”

“…[2][3][4][5][6][7] They are associated with Rolandic epilepsy 8 and mirror phenotypes on body mass index (BMI), head circumference (HC), and brain volume. [9][10][11][12] The deletion of the distal 16p11.2 220 kb BP2-BP3 locus (MIM: 613444) is likewise enriched in individuals with early-onset obesity and is also associated with developmental delay, intellectual disability, autism spectrum disorders (ASD), and schizophrenia. 3,[13][14][15][16] Moreover, the BP2-BP3 deletion and reciprocal duplication have mirror effects on BMI and HC, whereas the duplication of this interval, like the deletion, is associated with ASD.…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…Contrasting phenotypes are observed: deletions are associated with increased brain volume/macrocephaly and increased body mass index/obesity, while duplications are associated with decreased brain volume/microcephaly and decreased body mass index [129,133,134]. Structural brain alterations were also found in a dosage-dependent manner based on whether the 16p11.2 locus was deleted or duplicated [135]. Brain regions involved in reward circuitry such as the striatum, mediodorsal thalamus, orbitofrontal cortex, and insula had significantly greater gray matter volume in individuals with deletions compared with duplications.…”