Subcortical brain alterations in carriers of genomic copy number variants

Kumar, Kuldeep, Modenato, Claudia, Moreau, Clara, Ching, Christopher R.K., Harvey, Annabelle, Martin-Brevet, Sandra, Huguet, Guillaume, Jean-Louis, Martineau, Douard, Elise, Martin, Charles-Olivier, Younis, Nadine, Tamer, Petra, Maillard, Anne M., Rodriguez-Herreros, Borja, Pain, Aurélie, Kushan, Leila, Isaev, Dmitry, Alpert, Kathryn, Ragothaman, Anjani, Turner, Jessica A., Wang, Lei, Ho, Tiffany C., Schmaal, Lianne, Silva, Ana I. ORCID: https://orcid.org/0000-0002-1184-4909, van den Bree, Marianne B.M. ORCID: https://orcid.org/0000-0002-4426-3254, Linden, David E.J. ORCID: https://orcid.org/0000-0002-5638-9292, Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862, Hall, Jeremy ORCID: https://orcid.org/0000-0003-2737-9009, Lippé, Sarah, Dumas, Guillaume, Draganski, Bogdan, Gutman, Boris A., Sønderby, Ida E., Andreassen, Ole A., Schultz, Laura M., Almasy, Laura, Glahn, David C., Bearden, Carrie E., Thompson, Paul M. and Jacquemont, Sébastien 2023. Subcortical brain alterations in carriers of genomic copy number variants. The American Journal of Psychiatry 180 (9) , pp. 685-698. 10.1176/appi.ajp.20220304

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Abstract

Objective: Copy number variants (CNVs) are well-known genetic pleiotropic risk factors for multiple neurodevelopmental and psychiatric disorders (NPDs), including autism (ASD) and schizophrenia. Little is known about how different CNVs conferring risk for the same condition may affect subcortical brain structures and how these alterations relate to the level of disease risk conferred by CNVs. To fill this gap, the authors investigated gross volume, vertex-level thickness, and surface maps of subcortical structures in 11 CNVs and six NPDs. Methods: Subcortical structures were characterized using harmonized ENIGMA protocols in 675 CNV carriers (CNVs at 1q21.1, TAR, 13q12.12, 15q11.2, 16p11.2, 16p13.11, and 22q11.2; age range, 6–80 years; 340 males) and 782 control subjects (age range, 6–80 years; 387 males) as well as ENIGMA summary statistics for ASD, schizophrenia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, bipolar disorder, and major depression. Results: All CNVs showed alterations in at least one subcortical measure. Each structure was affected by at least two CNVs, and the hippocampus and amygdala were affected by five. Shape analyses detected subregional alterations that were averaged out in volume analyses. A common latent dimension was identified, characterized by opposing effects on the hippocampus/amygdala and putamen/pallidum, across CNVs and across NPDs. Effect sizes of CNVs on subcortical volume, thickness, and local surface area were correlated with their previously reported effect sizes on cognition and risk for ASD and schizophrenia. Conclusions: The findings demonstrate that subcortical alterations associated with CNVs show varying levels of similarities with those associated with neuropsychiatric conditions, as well distinct effects, with some CNVs clustering with adult-onset conditions and others with ASD. These findings provide insight into the long-standing questions of why CNVs at different genomic loci increase the risk for the same NPD and why a single CNV increases the risk for a diverse set of NPDs. Subcortical brain structures play a critical role in cognitive, affective, and social functions (1, 2). Large-scale international neuroimaging studies have shown that major neurodevelopmental and psychiatric disorders (NPDs) (3), including schizophrenia (4), major depressive disorder (MDD) (5), bipolar disorder (6), obsessive-compulsive disorder (OCD) (7), autism spectrum disorder (ASD) (8), and attention deficit hyperactivity disorder (ADHD) (9), are associated with alterations in subcortical structures (10–12). These case-control association studies have revealed small to moderate effect sizes on brain morphometry, which have been interpreted as a consequence of heterogeneity at the level of genetics and brain mechanisms (13–16). “Genetics-first” studies, in which participants are ascertained based on genetic etiology, can potentially overcome challenges posed by the genetic and mechanistic heterogeneity of behaviorally defined (idiopathic) NPDs (17–19). A growing body of literature demonstrates subcortical volumetric alterations associated with genetic risk for NPDs as conferred by copy number variants (CNVs). CNVs are major contributors to NPDs such as ASD and schizophrenia (15, 20) but show weaker associations with bipolar disorder (21, 22) and MDD (23). Among the CNVs included in this study, the largest increases in risk for schizophrenia have been documented for the 22q11.2 deletion (30- to 40-fold) followed by 16p11.2 duplication (10-fold), 1q21.1 deletion, and 15q11.2 deletion (1.5- to 2-fold) (3, 14, 15). ASD risk is highest for 16p11.2 deletions and duplications (10-fold), followed by 1q21.1 duplications and 22q11.2 duplications (3- to 4-fold) (3, 14, 17, 20). All CNVs affect cognitive ability, to varying degrees (decreases between 2.4 and 28.8 IQ points) (Table 1), with the exception of 15q11.2 and 13q12.12 duplications. TABLE 1. Genetic, cohort, and demographic characteristics of participants in the studya Enlarge table Previous studies have shown that CNVs including 1q21.1-distal (24), 16p11.2-proximal BP4-5 (25), 16p11.2-distal BP2-3 (26), 15q11.2 BP1-BP2 (27), and 22q11.2 (13) affect subcortical structures, with mild to large effect sizes (14). Recent studies have found a significant overlap between subcortical and cortical alterations associated with 22q11.2 deletion carriers and those associated with idiopathic schizophrenia as well as other psychiatric illnesses (13, 28). Beyond volumetric measurements, shape analyses of subcortical structures can capture differences that are predictive of disease status at a higher granularity (2, 29). Studies have typically focused on thickness, defined by the distance from the medial axis of each structure, and local surface area, which is a measure of surface contraction or expansion (13, 30). Both shape measures have been shown to be highly heritable (31, 32) and have been used to map subcortical variation in schizophrenia (30), ASD (29), MDD (33), and bipolar disorder (34). Thickness is a proxy for subregional volume changes, while the relationship between surface and volume depends on the local curvature of the region (30). For CNVs, subcortical analyses at the vertex level have been performed only in 22q11.2 deletion carriers (13), demonstrating multiple clusters of regional subcortical alterations, which were modulated by psychotic illness. Overall, little is known about how genetic variants conferring risk for psychiatric conditions affect subcortical structures. Previous neuroimaging studies have mainly focused on individual CNVs, making it challenging to directly compare MRI alterations across CNVs as well as to relate these MRI alterations to the level of disease risk conferred by CNVs. In particular, while multiple CNVs confer risk for the same psychiatric conditions (35, 36), it is unknown whether they are also associated with similar patterns of brain alterations underlain by a common latent dimension. Similarly, it has been shown that a common latent dimension can be identified across psychiatric diagnoses (37), and it is unknown whether a similar dimension may be observed for genetic risk. Our overall aim in this study was to systematically compare effect sizes and patterns of subcortical alterations associated with rare genetic risk for NPDs. Specifically, we aimed 1) to characterize subcortical volumetric and shape alterations in 11 CNVs, 2) to relate effect sizes of CNVs on subcortical metrics with previously reported effects of CNVs on risk for NPDs, and 3) to identify latent subcortical brain morphometry dimensions across CNVs and NPDs. To this end, we assembled the largest T1-weighted brain MRI data set across all recurrent CNVs (N=11) previously associated with varying levels of risk for psychiatric illness (Table 1), and characterized volume, three-dimensional surface, and thickness maps of subcortical structures. Effect sizes for six NPDs (ADHD, ASD, bipolar disorder, MDD, OCD, and schizophrenia) were obtained from previously published studies from the ENIGMA consortium.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Psychiatry Online
ISSN:	0002-953X
Last Modified:	08 Jul 2024 14:00
URI:	https://orca.cardiff.ac.uk/id/eprint/169339

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