1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive functio

Brain‐wide associations between white matter and age highlight the role of fornix microstructure in brain ageing

Unveiling the details of white matter (WM) maturation throughout ageing is a fundamental question for understanding the ageing brain. In an extensive comparison of brain age predictions and age-associations of WM features from different diffusion approaches, we analyzed UK Biobank diffusion magnetic resonance imaging (dMRI) data across midlife and older age (N = 35,749, 44.6–82.8 years of age). Conventional and advanced dMRI approaches were consistent in predicting brain age. WM-age associations indicate a steady microstructure degeneration with increasing age from midlife to older ages. Brain age was estimated best when combining diffusion approaches, showing different aspects of WM contributing to brain age. Fornix was found as the central region for brain age predictions across diffusion approaches in complement to forceps minor as another important region. These regions exhibited a general pattern of positive associations with age for intra axonal water fractions, axial, radial diffusivities, and negative relationships with age for mean diffusivities, fractional anisotropy, kurtosis. We encourage the application of multiple dMRI approaches for detailed insights into WM, and the further investigation of fornix and forceps as potential biomarkers of brain age and ageing.publishedVersio

The genetic architecture of the corpus callosum and its subregions

Background: Regional surface area and thickness of the cerebral cortex and volume of subcortical structures are highly heritable brain morphological features with complex genetic architectures, involving many common genetic variants with small effect sizes. However, the genetic architecture of the corpus callosum (CC) and its subregions remains largely unclear. We aim to determine the heritability and genetic architecture of CC volume and each subregion and the extent to which this overlaps with that of psychiatric disorders. Methods: Genetic and T1-weighted MRI data of 40,894 individuals from the UK-biobank was used to construct a multivariate GWAS. Here, we utilized a multivariate approach (Multivariate Omnibus Statistical Test, MOSTest) to assess the distributive effects of common variants across the five subregions of the CC (posterior, mid posterior, central, mid anterior and anterior) obtained by running the automatic subcortical segmentation algorithm in FreeSurfer 5.3. Gene-set enrichment analyses were performed using MAGMA. Linkage disequilibrium score regression was used to determine the SNP-based heritability of the CC and will be used to assess the genetic correlation between each subregion and a variety of psychiatric disorders. Results: Following MOSTest, 70 independent loci show pooled effects across the 5 subregions of the CC (p more than 5×10-8). Using LDSC, we found evidence to suggest that CC volume is heritable (h2SNP= 0.38, SE=0.03). Significant variants showed enrichment in pathways related to regulation of the nervous system and cell development, neurogenesis, and regulation of neuron differentiation. Gene-set analysis revealed 156 significant genes (p is less than 2.6x10-6). Many of the significant SNPs have been previously associated with white matter hyperintensity volume as well as a range of psychiatric disorders. Discussion: Here we provide the first preliminary evidence to suggest that volume of the CC is heritable. Gene set enrichment analyses identified pathways related to neuron development and neurogenesis, suggesting that CC alteration may have an independent developmental origin. Further investigation into the shared genetic architecture of CC subregions and psychiatric disorders may provide novel insight into disease manifestation

Anxiety modulates the relation between attention-deficit/hyperactivity disorder severity and working memory-related brain activity

Objectives: Individuals with attention-deficit/hyperactivity disorder (ADHD) often have heightened levels of anxiety, which has been associated with worse performance on working memory tasks. Knowledge of the neural pathways underlying the combined presence of ADHD and anxiety may aid in a better understanding of their co-occurrence. Therefore, we investigated how anxiety modulates the effect of ADHD severity on neural activity during a visuospatial working memory (VSWM) task.Methods: Neuroimaging data were available for 371 adolescents and young adults participating in the multicentre cohort study NeuroIMAGE (average age 17.1 years). We analysed the effects of ADHD severity, anxiety severity and their interaction on-task accuracy, and on neural activity associated with working memory (VSWM trials minus baseline), and memory load (high memory load trials minus low load trials).Results: Anxiety significantly modulated the relation between ADHD severity and neural activity in the cerebellum for the working memory contrast, and bilaterally in the striatum and thalamus for the memory load contrast.Conclusions: We found that ADHD with co-occurring anxiety is associated with lowered neural activity during a VSWM task in regions important for information gating. This fits well with previous theorising on ADHD with co-occurring anxiety, and illustrates the neurobiological heterogeneity of ADHD

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMACNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers—the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function

Embedding routine health care data in clinical trials:with great power comes great responsibility

Randomised clinical trials (RCTs) are vital for medical progress. Unfortunately, ‘traditional’ RCTs are expensive and inherently slow. Moreover, their generalisability has been questioned. There is considerable overlap in routine health care data (RHCD) and trial-specific data. Therefore, integration of RHCD in an RCT has great potential, as it would reduce the effort and costs required to collect data, thereby overcoming some of the major downsides of a traditional RCT. However, use of RHCD comes with other challenges, such as privacy issues, as well as technical and practical barriers. Here, we give a current overview of related initiatives on national cardiovascular registries (Netherlands Heart Registration, Heart4Data), showcasing the interrelationships between and the relevance of the different registries for the practicing physician. We then discuss the benefits and limitations of RHCD use in the setting of a pragmatic RCT from a cardiovascular perspective, illustrated by a case study in heart failure.</p

Embedding routine health care data in clinical trials:with great power comes great responsibility

Randomised clinical trials (RCTs) are vital for medical progress. Unfortunately, ‘traditional’ RCTs are expensive and inherently slow. Moreover, their generalisability has been questioned. There is considerable overlap in routine health care data (RHCD) and trial-specific data. Therefore, integration of RHCD in an RCT has great potential, as it would reduce the effort and costs required to collect data, thereby overcoming some of the major downsides of a traditional RCT. However, use of RHCD comes with other challenges, such as privacy issues, as well as technical and practical barriers. Here, we give a current overview of related initiatives on national cardiovascular registries (Netherlands Heart Registration, Heart4Data), showcasing the interrelationships between and the relevance of the different registries for the practicing physician. We then discuss the benefits and limitations of RHCD use in the setting of a pragmatic RCT from a cardiovascular perspective, illustrated by a case study in heart failure.</p