Biology subjects

Franke, B.

Publications and source records attributed to Franke, B..

53 records · Page 3Linked to original sources

bioRxiv2019

Localizing regions in the genome contributing to ADHD, aggressive and antisocial behavior

Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder, which in some cases occurs comorbid with aggressive and antisocial behavior (AGG; ASB). The three externalizing behaviors are moderately to highly heritable and are genetically correlated. However, the genomic regions underlying this correlation are unknown. In this study, we aimed to localize genetic loci shared between ADHD, AGG, and ASB, using two complementary approaches. GWAS summary statistics for ADHD, AGG, and ASB were used for (1) cross-trait gene-based meta-analysis association analyses and (2) local genetic correlation analyses to identify shared genetic loci. Results of both complementary methods were combined to retrieve overlapping genes. Biological functionality of prioritized genes was assessed by exploring gene expression patterns in brain tissues and testing for gene-based association with (subcortical) brain regions. We confirmed previous findings that ADHD, AGG, and ASB were positively genetically correlated at a global level. We identified eleven significant genes in cross-trait gene-based meta-analyses, 31 loci shared between traits; 34 genes were identified when both approaches were combined. This study emphasizes the complex genetic architecture underlying global genetic correlations at the locus level. Converging evidence from these cross-trait analyses highlights novel candidate genes underlying biological mechanisms shared by ADHD, AGG, and ASB.

genetics↗

bioRxiv2019

Brunner syndrome associated MAOA dysfunction in human iPSC derived dopaminergic neurons results in dysregulated NMDAR expression and increased network activity

Monoamine oxidase A (MAOA) is an enzyme that catalyzes the degradation of dopamine, noradrenaline, and serotonin. Regulation of monoamine neurotransmitter abundance through MAOA activity strongly affects motor control, emotion, and cognitive function. Mutations in MAOA cause Brunner Syndrome, which is characterized by impulsive aggressive behavior and mild intellectual disability (ID). The impaired MAOA activity in Brunner Syndrome patients results in bioamine aberration, but it is currently unknown how this affects neuronal function. MAOA is highly expressed in serotonergic and dopaminergic neurons, and dysfunction of both neurotransmission systems is associated with aggressive behavior in mice and humans. Research has so far mainly focused on the serotonergic system. Here, we generated human induced pluripotent stem cell-derived induced dopaminergic neurons (iDANs) from individuals with known MAOA mutations, to investigate MAOA-dependent effects on dopamine neuronal function in the context of Brunner Syndrome. We assessed iDAN lines from three patients and combined data from morphological analysis, gene expression, single-cell electrophysiology, and network analysis using micro-electrode arrays (MEAs). We observed mutation-dependent functional effects as well as overlapping changes in iDAN morphology. The most striking effect was a clear increase in N-methyl-D-aspartate (NMDA) receptor mRNA expression in all patient lines. A marked increase was also seen in coordinated network activity (network bursts) on the MEA in all patient lines, while single-cell intrinsic properties and spontaneous excitatory postsynaptic currents activity appeared normal. Together, our data indicate that dysfunction of MAOA leads to increased coordinated network activity in iDANs, possibly caused by increased synaptic NMDA receptor expression.

neuroscience↗

bioRxiv2019

Intellectual Disability-related genes increase ADHD risk and locomotor activity in Drosophila

ObjectiveAttention-Deficit/Hyperactivity Disorder (ADHD) is a common, highly heritable neuropsychiatric disorder. ADHD often co-occurs with Intellectual Disability (ID), and shared overlapping genetics have been suggested. This study aimed to identify novel ADHD genes by investigating whether genes carrying rare mutations linked to ID contribute to ADHD risk through common genetic variants. Validation and characterization of candidates were performed using Drosophila melanogaster.\n\nMethodCommon genetic variants in a diagnostic gene panel of 396 autosomal ID genes were tested for association with ADHD risk, through gene-set and gene-wide analyses, using ADHD meta-analytic data of the Psychiatric Genomics Consortium (n=19,210) for discovery and iPSYCH ADHD data for replication (n=37,076). The significant genes were functionally validated and characterized in Drosophila by assessing locomotor activity and sleep upon knockdown of those genes in brain circuits.\n\nResultsThe ID gene-set was significantly associated with ADHD risk in the discovery and replication data-sets. The three genes most consistently associated were MEF2C, ST3GAL3, and TRAPPC9. Performing functional characterization of the two evolutionary conserved genes in Drosophila melanogaster, we found their knockdown in dopaminergic (dMEF2) and circadian neurons (dTRAPPC9) to result in increased locomotor activity and reduced sleep, concordant with the human phenotype.\n\nConclusionsThis study reveals that a large set of ID-related genes contributes to ADHD risk through effects of common alleles. Utilizing this continuity, we identified TRAPPC9, MEF2C, and ST3GAL3 as novel ADHD candidate genes. Characterization in Drosophila suggests that TRAPPC9 and MEF2C contribute to ADHD-related behavior through distinct neural substrates.

genetics↗

bioRxiv2019

Discovering the shared biology of cognitive traits determined by genetic overlap

Investigating the contribution of biology to human cognition has assumed a bottom-up causal cascade where genes influence brain systems that activate, communicate, and ultimately drive behavior. Yet few studies have directly tested whether cognitive traits with overlapping genetic underpinnings also rely on overlapping brain systems. Here, we report a step-wise exploratory analysis of genetic and functional imaging overlaps among cognitive traits. We used twin-based genetic analyses in the human connectome project (HCP) dataset (N=486), in which we quantified the heritability of measures of cognitive functions, and tested whether they were driven by common genetic factors using pairwise genetic correlations. Subsequently, we derived activation maps associated with cognitive tasks via functional imaging meta-analysis in BrainMap (N=4484), and tested whether cognitive traits that shared genetic variation also exhibited overlapping brain activation. Our genetic analysis determined that six cognitive measures (card sorting, no-go continuous performance, fluid intelligence, processing speed, reading decoding and vocabulary comprehension) were heritable (0.3<h2<0.5), and genetically correlated with at least one other heritable cognitive measure (0.2<{rho}g<0.35). The meta-analysis showed that two genetically-correlated traits, card sorting and fluid intelligence ({rho}g=0.24), also had a significant brain activation overlap ({rho}perm=0.29). These findings indicate that fluid intelligence and executive functioning rely on overlapping biological features, both at the neural systems level and at the molecular level. The cross-disciplinary approach we introduce provides a concrete framework for data-driven quantification of biological convergence between genetics, brain function, and behavior in health and disease.

neuroscience↗

bioRxiv2019

Subcortical brain volume, regional cortical thickness and cortical surface area across attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD): findings from the ENIGMA-ADHD, -ASD, and -OCD working groups

ObjectiveAttention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders.\n\nMethodsStructural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures).\n\nResultsWe found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed.\n\nConclusionOur findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.

neuroscience↗

bioRxiv2019

Genetic overlap between obsessive-compulsive disorder, related symptoms in the population and insulin signaling: etiological implications

ObjectiveObsessive-compulsive symptoms (OCS) in the population have been linked to obsessive-compulsive disorder (OCD) in genetic and epidemiological studies. Insulin signaling has been implicated in OCD. We extend previous work by assessing genetic overlap between OCD, population-based OCS, and central nervous system (CNS) and peripheral insulin signaling.\n\nMethodsWe conducted genome-wide association studies (GWASs) in the population-based Philadelphia Neurodevelopmental Cohort (PNC, 650 children and adolescents) of the total OCS score and six OCS factors from an exploratory factor analysis of 22 questions. Subsequently, we performed polygenic risk score (PRS) analysis to assess shared genetic etiologies between clinical OCD (using GWAS data from the Psychiatric Genomics Consortium), the total OCS score and OCS factors. We then performed gene-set analyses with a set of OCD-linked genes centered around CNS insulin-regulated synaptic function and PRS analyses for five peripheral insulin signaling-related traits. For validation purposes, we explored data from the independent Spit for Science population cohort (5047 children and adolescents).\n\nResultsIn the PNC, we found a shared genetic etiology between OCD and impairment, contamination/cleaning and guilty taboo thoughts. In the Spit for Science cohort, we were able to validate the finding for contamination/cleaning, and additionally observed genetic sharing between OCD and symmetry/counting/ordering. The CNS insulin-linked gene-set associated with symmetry/counting/ordering. We also identified genetic sharing between peripheral insulin signaling-related traits (type 2 diabetes and the blood levels of HbA1C, fasting insulin and 2 hour glucose) and OCD as well as certain OCS.\n\nConclusionsOCD, OCS in the population and insulin-related traits share genetic risk factors, indicating a common etiological mechanism underlying somatic and psychiatric disorders.

genetics↗

bioRxiv2019

Different Whole-Brain Functional Connectivity Correlates of Reactive-Proactive Aggression and Callous-Unemotional Traits in Disruptive Children and Adolescents

BackgroundDisruptive behavior in children and adolescents can manifest itself in reactive (RA) and proactive (PA) aggression and is modulated by callous-unemotional (CU) traits and comorbidity. Research on aggression subtype-specific neural correlates is limited and the role of comorbid symptoms largely neglected.\n\nMethodsThe current multi-center study extended previous efforts by investigating unrestricted resting state functional connectivity (rsFC) alterations. The large sample (n = 207) of children and adolescents aged 8 - 18 years (mean age = 13.30 {+/-} 2.60 years) included 118 cases with disruptive behavior (80 diagnosed with Oppositional Defiant Disorder and/or Conduct Disorder) and 89 controls. Attention-deficit/hyperactivity disorder (ADHD) and anxiety symptoms were added as covariates. We measured changes in global and local voxel-to-voxel rsFC using functional magnetic resonance imaging at 3T (mean acquisition time = 8 min 25 sec).\n\nResultsCompared to controls, cases demonstrated altered rsFC including frontal areas when anxiety but not ADHD symptoms were considered. Within cases, RA and PA scores related to changes in global and local rsFC in central gyrus and precuneus previously linked to aggression-related impairments. CU trait severity correlated with global rsFC alterations including inferior and middle temporal gyrus implicated in empathy, emotion, and reward-related activity. Importantly, most observed aggression subtype-specific patterns could only be identified when ADHD and anxiety problems were also accounted for.\n\nConclusionsThe current study clarifies that distinct though overlapping brain connectivity measures can disentangle differing manifestations of aggressive behavior. Moreover, our results highlight the importance of considering comorbid symptoms for detecting aggression-related rsFC alterations.

neuroscience↗

bioRxiv2019

Cross-disorder genetic analyses implicate dopaminergic signaling as a biological link between Attention-Deficit/Hyperactivity Disorder and obesity measures

Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity are frequently comorbid, genetically correlated, and share brain substrates. The biological mechanisms driving this association are unclear, but candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the genetic link between ADHD and obesity measures and investigate associations of overlapping genes with brain volumes. We tested the association of dopaminergic and circadian rhythm gene sets with ADHD, body mass index (BMI), and obesity (using GWAS data of N=53,293, N=681,275, and N=98,697, respectively). We then conducted genome-wide ADHD-BMI and ADHD-obesity gene-based meta-analyses, followed by pathway enrichment analyses. Finally, we tested the association of ADHD-BMI overlapping genes with brain volumes (primary GWAS data N=10,720-10,928; replication data N=9,428). The dopaminergic gene set was associated with both ADHD (P=5.81x10-3) and BMI (P=1.63x10-5), the circadian rhythm was associated with BMI (P=1.28x10-3). The genome-wide approach also implicated the dopaminergic system, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was enriched in both ADHD-BMI and ADHD-obesity results. The ADHD-BMI overlapping genes were associated with putamen volume (P=7.7x10-3; replication data P=3.9x10-2) - a brain region with volumetric reductions in ADHD and BMI and linked to inhibitory control. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling and involving the putamen, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering shared etiological factors underlying the frequently observed ADHD-obesity comorbidity may have important implications in terms of prevention and/or efficient treatment of these conditions.

genetics↗

bioRxiv2019

Machine Learning Classification of Attention-Deficit/Hyperactivity Disorder Using Structural MRI Data

ADHD affects 5% of children world-wide. Of these, two-thirds continue to have impairing symptoms of ADHD into adulthood. Although a large literature implicates structural brain differences in the pathophysiology of the disorder, it is not clear if adults with ADHD have similar neuroanatomical impairments as those seen in children with recent reports from the large ENIGMA-ADHD consortium finding structural abnormalities for children but not for adults. This paper uses deep learning neural network classification models to determine if there are neuroanatomical changes in the brains of children with ADHD that are also observed for adult ADHD, and vice versa. We found that structural MRI data can significantly separate ADHD from control participants for both children and adults. Consistent with the prior reports from ENIGMA-ADHD, prediction performance and effect sizes were better for the child than the adult samples. The model trained on adult samples significantly predicted ADHD in the child sample, suggesting that our model learned anatomical features that common to ADHD in childhood and adulthood. These results support the continuity of ADHDs pathophysiology from childhood to adulthood. In addition, our work demonstrates a novel use of neural network classification models to test hypotheses about developmental continuity.

bioinformatics↗

bioRxiv2018

Reactive/proactive aggression specific cortical and subcortical alterations in children and adolescents with disruptive behavior

ObjectiveMaladaptive aggression, as present in conduct disorder (CD) and, to a lesser extent, oppositional defiant disorder (ODD), has been associated with structural alterations in various brain regions, such as ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), amygdala, insula and ventral striatum. Although aggression can be subdivided into reactive and proactive subtypes, no neuroimaging studies have yet investigated if any structural brain alterations are associated with either of the subtypes specifically. Here we investigated this association in predefined regions of interest.\n\nMethodT1-weighted magnetic resonance images were acquired from 158 children and adolescents with aggressive behavior (ODD/CD) and 96 controls in a multi-centre study. Aggression subtypes were assessed by questionnaires. Cortical volume and subcortical volumes and shape were determined using Freesurfer and the FMRIB integrated registration and segmentation tool. Associations between volumes and continuous measures of aggression were established using multilevel linear mixed effects models.\n\nResultsIn cases only proactive aggression was negatively associated with amygdala volume (b=-11.82, p=0.05), while reactive aggression was negatively associated with insula volume (b=-46.41, p=0.01). Classical group comparison showed that children and adolescents with aggressive behavior had smaller volumes than controls in (bilateral) ventral striatum (p=0.003), ACC (p=0.01), and vmPFC (p=0.003) with modest effect sizes.\n\nConclusionsAggression was associated with reduced volume in brain regions involved in decision making. Negative associations were found between reactive aggression and volumes in regions involved in threat responsivity and between proactive aggression and regions linked to empathy. This provides evidence for aggression subtype-specific alterations in brain structure.

neuroscience↗

bioRxiv2018

Aggression Subtypes Relate to Distinct Resting State Functional Connectivity in Disruptive Children and Adolescents

ObjectiveThere is increasing evidence to suggest altered resting state functional connectivity (rsFC) in adolescents with conduct problems. However, no rsFC studies have addressed the effects of reactive and proactive aggression. Herein, we examined the associations between these aggression subtypes along with subdimensions of callous-unemotional (CU) traits and rsFC using predefined seeds in aggression-related salience network (SN) and default mode network (DMN).\n\nMethodAggression subtype-specific whole-brain rsFC of SN and DMN seeds was investigated in a resting state sequence (mean acquisition time = 8 min 25 sec) acquired from 207 children and adolescents of both sexes aged 8 - 18 years (mean age (SD) = 13.30 (2.60) years; range = 8.02 - 18.35) in a multi-center study. One hundred eighteen individuals exhibited disruptive behavior (conduct disorder/oppositional defiant disorder) with different levels of comorbid ADHD symptoms, 89 were healthy.\n\nResultsCompared to healthy controls, cases demonstrated reduced DMN and - after controlling for ADHD scores - SN seed-based rsFC with left hemispheric frontal clusters. We found increased and distinct aggression-subtype specific rsFC patterns in brain regions linked to processes like emotion, empathy, moral, cognitive control, and decision-making. Specifically, reactive and proactive aggression correlated with distinct SN and DMN seed-based rsFC patterns. CU dimensions led to different DMN and SN rsFC with clusters including frontal, parietal, and cingulate areas, with uncaring-related clusters extended to cerebellar regions.\n\nConclusionsThis first study investigating reactive and proactive aggression along with CU dimensions reveals new subtype-specific whole-brain rsFC patterns, extending the knowledge of neural networks to further distinct forms of disruptive behavior.

neuroscience↗

bioRxiv2018

Genetic control of variability in subcortical and intracranial volumes

Sensitivity to external demands is essential for adaptation to dynamic environments, but comes at the cost of increased risk of adverse outcomes when facing poor environmental conditions. Here, we apply a novel methodology to perform genome-wide association analysis of mean and variance in nine key brain features (accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, intracranial volume and cortical thickness), integrating genetic and neuroanatomical data from a large lifespan sample (n=25,575 individuals; 8 to 89 years, mean age 51.9 years). We identify genetic loci associated with phenotypic variability in cortical thickness, thalamus, pallidum, and intracranial volumes. The variance-controlling loci included genes with a documented role in brain and mental health and were not associated with the mean anatomical volumes. This proof-of-principle of the hypothesis of a genetic regulation of brain volume variability contributes to establishing the genetic basis of phenotypic variance (i.e., heritability), allows identifying different degrees of brain robustness across individuals, and opens new research avenues in the search for mechanisms controlling brain and mental health.

neuroscience↗

bioRxiv2018

Genetics of brain age suggest an overlap with common brain disorders

Numerous genetic and environmental factors contribute to psychiatric disorders and other brain disorders. Common risk factors likely converge on biological pathways regulating the optimization of brain structure and function across the lifespan. Here, using structural magnetic resonance imaging and machine learning, we estimated the gap between brain age and chronological age in 36,891 individuals aged 3 to 96 years, including individuals with different brain disorders. We show that several disorders are associated with accentuated brain aging, with strongest effects in schizophrenia, multiple sclerosis and dementia, and document differential regional patterns of brain age gaps between disorders. In 16,269 healthy adult individuals, we show that brain age gap is heritable with a polygenic architecture overlapping those observed in common brain disorders. Our results identify brain age gap as a genetically modulated trait that offers a window into shared and distinct mechanisms in different brain disorders.

neuroscience↗

bioRxiv2018

Brain scans from 21297 individuals reveal the genetic architecture of hippocampal subfield volumes

The hippocampus is a heterogeneous structure, comprising histologically distinguishable subfields. These subfields are differentially involved in memory consolidation, spatial navigation and pattern separation, complex functions often impaired in individuals with brain disorders characterized by reduced hippocampal volume, including Alzheimers disease (AD) and schizophrenia. Given the structural and functional heterogeneity of the hippocampal formation, we sought to characterize the subfields genetic architecture. T1-weighted brain scans (n=21297, 16 cohorts) were processed with the hippocampal subfields algorithm in FreeSurfer v6.0. We ran a genome-wide association analysis on each subfield, covarying for total hippocampal volume. We further calculated the single nucleotide polymorphism (SNP)-based heritability of twelve subfields, as well as their genetic correlation with each other, with other structural brain features, and with AD and schizophrenia. All outcome measures were corrected for age, sex, and intracranial volume. We found 15 unique genome-wide significant loci across six subfields, of which eight had not been previously linked to the hippocampus. Top SNPs were mapped to genes associated with neuronal differentiation, locomotor behaviour, schizophrenia and AD. The volumes of all the subfields were estimated to be heritable (h2 from .14 to .27, all p< 1x10-16) and clustered together based on their genetic correlations compared to other structural brain features. There was also evidence of genetic overlap of subicular subfield volumes with schizophrenia. We conclude that hippocampal subfields have partly distinct genetic determinants associated with specific biological processes and traits. Taking into account this specificity may increase our understanding of hippocampal neurobiology and associated pathologies.

genetics↗

bioRxiv2017

Genetic markers of ADHD-related variations in intracranial volume

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology, where genetic risk is hypothesized to be mediated by alterations in structure and function of diverse brain networks. We tested one aspect of this hypothesis by investigating the genetic overlap between ADHD (n=55,374) and (mainly subcortical) brain volumes (n=11,221-24,704), using the largest publicly available studies. At the level of common variant genetic architecture, we discovered a significant negative genetic correlation between ADHD and intracranial volume (ICV). Meta-analysis of individual variants found significant loci associated with both ADHD risk and ICV; additional loci were identified for ADHD and amygdala, caudate nucleus, and putamen volumes. Gene-set analysis in the ADHD-ICV meta-analytic data showed significant association with variation in neurite outgrowth-related genes. In summary, our results suggest new hypotheses about biological mechanisms involved in ADHD etiology and highlight the need to study additional brain parameters.

genetics↗

bioRxiv2017

A genetic investigation of sex bias in the prevalence of attention deficit hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is 2-7 times more common in males than females. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. We analyzed genome-wide common variants from the Psychiatric Genomics Consortium and iPSYCH Project (20,183 cases, 35,191 controls) and Swedish population-registry data (N=77,905 cases, N=1,874,637 population controls). We find strong genetic correlation for ADHD across sex and no mean difference in polygenic burden across sex. In contrast, siblings of female probands are at an increased risk of ADHD, compared to siblings of male probands. The results also suggest that females with ADHD are at especially high risk of comorbid developmental conditions. Overall, this study supports a greater familial burden of risk in females with ADHD and some clinical and etiological heterogeneity. However, autosomal common variants largely do not explain the sex bias in ADHD prevalence.

genetics↗

bioRxiv2017

Do Candidate Genes Affect the Brain’s White Matter Microstructure? Large-Scale Evaluation of 6,165 Diffusion MRI Scans

AbstractSusceptibility genes for psychiatric and neurological disorders - including APOE, BDNF, CLU,CNTNAP2, COMT, DISC1, DTNBP1, ErbB4, HFE, NRG1, NTKR3, and ZNF804A - have been reported to affect white matter (WM) microstructure in the healthy human brain, as assessed through diffusion tensor imaging (DTI). However, effects of single nucleotide polymorphisms (SNPs) in these genes explain only a small fraction of the overall variance and are challenging to detect reliably in single cohort studies. To date, few studies have evaluated the reproducibility of these results. As part of the ENIGMA-DTI consortium, we pooled regional fractional anisotropy (FA) measures for 6,165 subjects (CEU ancestry N=4,458) from 11 cohorts worldwide to evaluate effects of 15 candidate SNPs by examining their associations with WM microstructure. Additive association tests were conducted for each SNP. We used several meta-analytic and mega-analytic designs, and we evaluated regions of interest at multiple granularity levels. The ENIGMA-DTI protocol was able to detect single-cohort findings as originally reported. Even so, in this very large sample, no significant associations remained after multiple-testing correction for the 15 SNPs investigated. Suggestive associations (1.3x10-4 < p < 0.05, uncorrected) were found for BDNF, COMT, and ZNF804A in specific tracts. Meta-and mega-analyses revealed similar findings. Regardless of the approach, the previously reported candidate SNPs did not show significant associations with WM microstructure in this largest genetic study of DTI to date; the negative findings are likely not due to insufficient power. Genome-wide studies, involving large-scale meta-analyses, may help to discover SNPs robustly influencing WM microstructure.

neuroscience↗