Abstract
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 (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, 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 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, 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.
Highlights
Carriers of large recurrent copy number variants (CNVs) are at increased risk for developing autism spectrum disorders (ASD), schizophrenia or intellectual disability [1]
In the ENIGMA-CNV discovery data set, we identified 12 16p11.2 distal deletion carriers and 12 duplication carriers scanned at 14 Magnetic resonance imaging (MRI) scanners, and 6882 non-carriers investigated at the same MRI scanners
Most CNV carriers exhibited the minimal 16p11.2 distal CNV type (BP2–BP3) (Fig. 1), four CNVs were of the extended type (BP1–BP3) and six CNVs extended into the 16p11.2 proximal region (BP1–BP5) (Supplementary Table 2, Supplementary Figure 1)
Summary
Carriers of large recurrent copy number variants (CNVs) are at increased risk for developing autism spectrum disorders (ASD), schizophrenia or intellectual disability [1]. The deletion is associated with obesity [26, 27], intellectual disability [26] and schizophrenia [20, 22] and the duplication has been associated with lower body mass index (BMI) [17, 31] Both 16p11.2 distal CNVs are associated with autism spectrum disorder [17] and have been found in individuals with epilepsy [23]. Large effect-size CNVs conferring risk for neurodevelopmental disorders including major psychiatric disorders [35] are rare (
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