Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study

Abstract

BACKGROUND: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure. METHODS: Using voxel-and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV. RESULTS: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion . control . duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion . control; Cohen's d . 1), the superior and middle temporal gyri (deletion , control; Cohen's d , 21), and the caudate and hippocampus (control . duplication; 20.5 . Cohen's d . 21). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results. CONCLUSIONS: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria. Autism spectrum disorder (ASD) and related neurodevelopmental disorders are defined behaviorally and characterized by a significant clinical and etiologic heterogeneity. As a consequence, investigating ASD under the assumption of an underlying homogeneous condition has resulted in controversial findings in the field of neuroimaging (1). Increased brain growth early in development (2-4) and alterations of many regional brain volumes (5) have been implicated in ASD, but results have proven difficult to replicate (1,(6)(7)(8).To mitigate some of these issues, cohorts of individuals with shared genetic risk factors have been assembled to minimize the noise introduced by etiologic and biological heterogeneity (9). Such a "genetic-first" study design provides the opportunity to investigate a given neurodevelopmental risk (and associated mechanism) shared by individuals who carry the same genetic etiology irrespective of the psychiatric diagnosis.Copy number variants (CNVs) at the 16p11.2 (breakpoints 4-5, 29.6-30.2 Mb-hg19) (10) are among the most frequent risk factors for neurodevelopmental and psychiatric conditions.

The human-specific BOLA2 duplication modifies iron homeostasis and anemia predisposition in chromosome 16p11.2 autism patients

“…Among these variants, 600 kbp deletions and duplications with breakpoints BP4 and BP5 are among the most frequent genetic causes of neurodevelopmental and psychiatric disorders (Weiss et al 2008;McCarthy et al 2009;Zufferey et al 2012;D'Angelo et al 2016;Marshall et al 2017). They are also associated in a dose-dependent manner with head circumference, body mass index, age at menarche, and the size of brain structures associated with reward, language, and social cognition (Shinawi et al 2010;Walters et al 2010;Jacquemont et al 2011;Maillard et al 2015;D'Angelo et al 2016;Martin-Brevet et al 2018) (Männik et al, unpublished). BP4-BP5 rearrangements are mediated by Homo sapiens sapiens-specific duplications.…”

Leveraging biobank-scale rare and common variant analyses to identify ASPHD1 as the main driver of reproductive traits in the 16p11.2 locus

“…By recording timing of first ovulation in females, we noted a reciprocal effect on sexual maturation that, similar to weight [31,32], was inverted Sexual development in mammals is regulated by hormonal interplay between hypothalamus, pituitary gland and gonads. We used human MRI data [16,17,33] to assess possible 16p11.2 dosage-dependent brain anatomy changes. Given our strong a priori hypothesis of an impaired neuroendocrine axis, we restricted the search volume to a 5 mm sphere centered on the hypothalamic region.…”

“…Human structural MRI data were acquired, processed and analyzed as described [16,17,33]. The mass-univariate statistical analysis of whole-brain volume maps was performed in 146 postpubertal individuals as described [34].…”

“…They also impact satiety response and BMI in a dosage-dependent manner [13][14][15]. Correspondingly, 16p11.2 gene dosage affects head circumference, and specifically, the size of brain structures associated with reward, language and social cognition [9,13,[15][16][17]. Genomewide association studies (GWAS) have identified reproducible associations between common SNPs of the 16p11.2 interval and BMI [18], schizophrenia [19,20] and age at menarche (AaM) [21][22][23].…”

Mapping causal pathways from genetics to neuropsychiatric disorders using genome‐wide imaging genetics: Current status and future directions

“…Genetic association studies continue to identify both common and rare variants that impact brain structures at the gross anatomical level. [124][125][126] MRI is suited to measure gross structural traits of intracranial volume and regional phenotypes like hippocampal volume or cortical surface area and thickness. [6][7][8]74,[81][82][83] These phenotypes can be measured in large numbers of living humans at a relatively affordable cost.…”