Neurodevelopmental disorders have a heritable component and are associated with region specific alterations in brain anatomy. However, it is unclear how genetic risks for neurodevelopmental disorders ...are translated into spatially patterned brain vulnerabilities. Here, we integrated cortical neuroimaging data from patients with neurodevelopmental disorders caused by genomic copy number variations (CNVs) and gene expression data from healthy subjects. For each of the six investigated disorders, we show that spatial patterns of cortical anatomy changes in youth are correlated with cortical spatial expression of CNV genes in neurotypical adults. By transforming normative bulk-tissue cortical expression data into cell-type expression maps, we link anatomical change maps in each analysed disorder to specific cell classes as well as the CNV-region genes they express. Our findings reveal organizing principles that regulate the mapping of genetic risks onto regional brain changes in neurogenetic disorders. Our findings will enable screening for candidate molecular mechanisms from readily available neuroimaging data.
The amygdala and hippocampus are two adjacent allocortical structures implicated in sex-biased and developmentally-emergent psychopathology. However, the spatiotemporal dynamics of ...amygdalo-hippocampal development remain poorly understood in healthy humans. The current study defined trajectories of volume and shape change for the amygdala and hippocampus by applying a multi-atlas segmentation pipeline (MAGeT-Brain) and semi-parametric mixed-effects spline modeling to 1,529 longitudinally-acquired structural MRI brain scans from a large, single-center cohort of 792 youth (403 males, 389 females) between the ages of 5 and 25 years old. We found that amygdala and hippocampus volumes both follow curvilinear and sexually dimorphic growth trajectories. These sex-biases were particularly striking in the amygdala: males showed a significantly later and slower adolescent deceleration in volume expansion (at age 20 years) than females (age 13 years). Shape analysis localized significant hot-spots of sex-biased anatomical development in sub-regional territories overlying rostral and caudal extremes of the CA1/2 in the hippocampus, and the centromedial nuclear group of the amygdala. In both sexes, principal components analysis revealed close integration of amygdala and hippocampus shape change along two main topographically-organized axes – low vs. high areal expansion, and early vs. late growth deceleration. These results (i) bring greater resolution to our spatiotemporal understanding of amygdalo-hippocampal development in healthy males and females, and (ii) uncover focal sex-differences in the structural maturation of the brain components that may contribute to differences in behavior and psychopathology that emerge during adolescence.
•Large-scale longitudinal single center study of volume and shape development for amygdala and hippocampus between childhood and early adulthood.•Sex-differences in trajectories of anatomical maturation with delayed deceleration of amygdala growth in males relative to females.•Localization of sex-differences in regional anatomical maturation within amygdala and hippocampus.•Discovery of two principle spatio-temporal components of coordinated shape change across the amygdala and hippocampus in both sexes.
The morphology of cells is dynamic and mediated by genetic and environmental factors. Characterizing how genetic variation impacts cell morphology can provide an important link between disease ...association and cellular function. Here, we combine genomic sequencing and high-content imaging approaches on iPSCs from 297 unique donors to investigate the relationship between genetic variants and cellular morphology to map what we term cell morphological quantitative trait loci (cmQTLs). We identify novel associations between rare protein altering variants in WASF2, TSPAN15, and PRLR with several morphological traits related to cell shape, nucleic granularity, and mitochondrial distribution. Knockdown of these genes by CRISPRi confirms their role in cell morphology. Analysis of common variants yields one significant association and nominate over 300 variants with suggestive evidence (P < 10
) of association with one or more morphology traits. We then use these data to make predictions about sample size requirements for increasing discovery in cellular genetic studies. We conclude that, similar to molecular phenotypes, morphological profiling can yield insight about the function of genes and variants.
Systemic lupus erythematosus is a clinically heterogeneous autoimmune disease. A number of genetic loci that increase lupus susceptibility have been established. This study examines if these genetic ...loci also contribute to the clinical heterogeneity in lupus.
4001 European-derived, 1547 Hispanic, 1590 African-American and 1191 Asian lupus patients were genotyped for 16 confirmed lupus susceptibility loci. Ancestry informative markers were genotyped to calculate and adjust for admixture. The association between the risk allele in each locus was determined and compared in patients with and without the various clinical manifestations included in the ACR criteria.
Renal disorder was significantly correlated with the lupus risk allele in ITGAM (p=5.0 × 10(-6), OR 1.25, 95% CI 1.12 to 1.35) and in TNFSF4 (p=0.0013, OR 1.14, 95% CI 1.07 to 1.25). Other significant findings include the association between risk alleles in FCGR2A and malar rash (p=0.0031, OR 1.11, 95% CI 1.17 to 1.33), ITGAM and discoid rash (p=0.0020, OR 1.20, 95% CI 1.06 to 1.33), STAT4 and protection from oral ulcers (p=0.0027, OR 0.89, 95% CI 0.83 to 0.96) and IL21 and haematological disorder (p=0.0027, OR 1.13, 95% CI 1.04 to 1.22). All these associations are significant with a false discovery rate of <0.05 and pass the significance threshold using Bonferroni correction for multiple testing.
Signifi cant associations were found between clinical manifestations and the FCGR2A, ITGAM, STAT4, TNSF4 and IL21 genes. The findings suggest that genetic profiling might be a useful tool to predict disease manifestations in lupus patients in the future.
With that in mind, we have drawn on our summer research experiences to propose tips on how to approach all aspects of a summer internship, including planning ahead, navigating professional ...relationships, and maximizing impact, among others. Biological systems often have mathematical models that represent the system over time-neurons, cardiac cells, circadian rhythms, gene networks, and metabolic processes all can be represented using sets of differential equations. Learning how to implement your related model and create simulations in a programming language will not only build your understanding of your research topic, but also help discover new dynamics of the biological system. Balance reading and doing Understanding scientific literature is an integral part of the research process, and a summer research position provides an opportune time to strengthen your reading skills.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Autism is a heterogeneous group of diagnoses, including both individuals with co-existing intellectual disability (ID) and individuals with average or above average intellectual quotient (IQ). Autism ...is highly heritable and has been associated with multiple classes of genetic variation. De novo single nucleotide and structural variation that increase the probability of an autism diagnosis are often associated with ID or decreased IQ. In contrast, inherited genetic associations to autism are on average IQ increasing. Given the potentially different genetic architectures of autism with (w/) and without (w/o) ID, we conducted a stratified genome-wide association study (GWAS) to investigate the genetic signatures of those subgroups.
We analyzed 1,685 trios from Simons Simplex Collection (SSC) and 6,971 trios from Simons Powering Autism Research for Knowledge (SPARK). Intellectual disability in SSC was defined as IQ.
The GWAS meta-analysis included 4,357 autism w/o ID trios and 3,993 autism w/ ID trios. We observed one genome-wide-significant locus in the autism w/ ID GWAS (lead SNP: rs12994053; odds ratio = 1.23; P = 3.50e-9), close to the gene ST3GAL5. The SNP heritabilities of autism w/o ID (0.17; SE=0.03) and autism w/ ID (0.16; SE=0.03) were similar, with a high degree of genetic correlation between them (0.81; P=2.37e-7). Autism w/o ID was positively genetically correlated with educational attainment (0.26; P=2.10e-8) and intelligence (0.24; P=5.00e-4). Autism w/ ID was positively genetically correlated with educational attainment (0.18; P=2.00e-4) but not with intelligence (0.09; P=0.21).
We report a stratified GWAS meta-analysis of autism w/ and w/o ID in SSC and SPARK. Although the two subgroups have similar SNP heritability and a high degree of genetic correlation, we observed suggestive evidence that autism w/ and w/o ID have different genetic correlation profiles with intelligence. As ID alone is negatively genetically correlated with intelligence, the lack of association between autism w/ ID and intelligence strongly suggests that autism and ID together are genetically different from ID alone. This difference has implications for both research and clinical nosology. Studying the shared and distinct genetic signature of autism w/ and w/o ID might provide an opportunity to parse the heterogeneity and uncover new biological insights into neurodevelopmental variability.
Childhood socioeconomic status (SES) impacts cognitive development and mental health, but its association with human structural brain development is not yet well characterized. Here, we analyzed 1243 ...longitudinally acquired structural MRI scans from 623 youth (299 female/324 male) to investigate the relation between SES and cortical and subcortical morphology between ages 5 and 25 years. We found positive associations between SES and total volumes of the brain, cortical sheet, and four separate subcortical structures. These associations were stable between ages 5 and 25. Surface-based shape analysis revealed that higher SES is associated with areal expansion of lateral prefrontal, anterior cingulate, lateral temporal, and superior parietal cortices and ventrolateral thalamic, and medial amygdalo-hippocampal subregions. Meta-analyses of functional imaging data indicate that cortical correlates of SES are centered on brain systems subserving sensorimotor functions, language, memory, and emotional processing. We further show that anatomical variation within a subset of these cortical regions partially mediates the positive association between SES and IQ. Finally, we identify neuroanatomical correlates of SES that exist above and beyond accompanying variation in IQ. Although SES is clearly a complex construct that likely relates to development through diverse, nondeterministic processes, our findings elucidate potential neuroanatomical mediators of the association between SES and cognitive outcomes.
Childhood socioeconomic status (SES) has been associated with developmental disparities in mental health, cognitive ability, and academic achievement, but efforts to understand underlying SES-brain relationships are ongoing. Here, we leverage a unique developmental neuroimaging dataset to longitudinally map the associations between SES and regional brain anatomy at high spatiotemporal resolution. We find widespread associations between SES and global cortical and subcortical volumes and surface area and localize these correlations to a distributed set of cortical, thalamic, and amygdalo-hippocampal subregions. Anatomical variation within a subset of these regions partially mediates the positive relationship between SES and IQ. Our findings help to localize cortical and subcortical systems that represent candidate biological substrates for the known relationships between SES and cognition.
Although waiting for a reward reduces or discounts its value, some people have a stronger tendency to wait for larger rewards and forgo smaller-but-immediate rewards. This ability to delay ...gratification is captured by individual differences in so-called intertemporal choices in which individuals are asked to choose between larger-but-delayed versus smaller-but-immediate rewards. The current study used event-related potentials (ERPs) to examine whether enhancement in two neurocognitive processes, outcome anticipation and outcome evaluation, modulate individual variability in intertemporal responses. After completing a behavioral intertemporal choice task, 34 participants performed an ERP gambling task. From this ERP task, we separately examined individual differences in outcome anticipation (stimulus-preceding negativity; SPN), early outcome valuation (feedback-related negativity; FRN), and late outcome evaluation (P3). We observed that both elevated outcome-anticipation (SPN) and late outcome-evaluation (P3) neural processes predicted a stronger preference toward larger-but-delayed rewards. No relationship was observed between intertemporal responses and early outcome evaluation (FRN), indicating that the relationship between outcome evaluation and intertemporal responses was specific to the late outcome-evaluation processing stream. Moreover, multiple regression analyses indicated that the SPN and P3 independently modulate individual differences in intertemporal responses, suggesting separate mechanisms underlie the relationship between these two neurocognitive processes and intertemporal responses. Accordingly, we identify two potential neurocognitive modulators of individual variability in intertemporal responses. We discuss the mechanisms underlying these modulators in terms of anticipation-related processing (SPN) and a saliency bias toward gain (compared to loss) outcomes (P3).
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