Biology subjects

Klein, M.

Publications and source records attributed to Klein, M..

66 records · Page 4Linked to original sources

bioRxiv2020

Rare protein coding variants implicate genes involved in risk of suicide death

Suicide death is a worldwide health crisis, claiming close to 800,000 lives per year. Recent evidence suggests that prediction and prevention challenges may be aided by discoveries of genetic risk factors. Here we focus on the role of rare (MAF <1%), putatively functional single nucleotide polymorphisms (SNPs) in suicide death using the large genetic resources available in the Utah Suicide Genetic Risk Study (USGRS). We conducted a single-variant association analysis of 30,377 rare putatively functional SNPs present on the PsychArray genotyping array in 2,672 USGRS suicides of non-Finnish European (NFE) ancestry and 51,583 publicly available NFE controls from gnomAD, with additional follow-up analyses using an independent control sample of 21,324 NFE controls from the Psychiatric Genomics Consortium. SNPs underwent rigorous quality control, and among SNPs meeting significance thresholds, we considered only those that were validated in sequence data. We identified five novel, high-impact, rare SNPs with significant associations with suicide death (SNAPC1, rs75418419; TNKS1BP1, rs143883793; ADGRF5, rs149197213; PER1, rs145053802; and ESS2, rs62223875). Both PER1 and SNAPC1 have other supporting gene-level evidence of suicide risk, and an association with bipolar disorder has been reported for PER1 and with schizophrenia for PER1, TNKS1BP1, and ESS2. Three genes (PER1, TNKS1BP1, and ADGRF5), with additional genes implicated by GWAS studies on suicidal behavior, showed significant enrichment in immune system, homeostatic and signal transduction processes. Pain, depression, and accidental trauma were the most prevalent phenotypes in electronic medical record data for the categories assessed. These findings suggest an important role for rare variants in suicide risk and provide new insights into the genetic architecture of suicide death. Furthermore, we demonstrate the added utility of careful assessment of genotyping arrays in rare variant discovery.

genetics↗

bioRxiv2019

From rare Copy Number Variations to biological processes in ADHD

AimAttention-deficit/hyperactivity disorder (ADHD) is a highly heritable psychiatric disorder. The objective of this study was to define ADHD-associated candidate genes, and their associated molecular modules and biological themes, based on the analysis of rare genetic variants.\n\nMethodsWe combined data from 11 published copy number variation (CNV) studies in 6176 individuals with ADHD and 25026 controls and prioritized genes by applying an integrative strategy based on criteria including recurrence in ADHD individuals, absence in controls, complete coverage in copy number gains, and presence in the minimal region common to overlapping CNVs, as well as on protein-protein interactions and information from cross-species genotype-phenotype annotation.\n\nResultsWe localized 2241 eligible genes in the 1532 reported CNVs, of which we classified 432 as high-priority ADHD candidate genes. The high-priority ADHD candidate genes were significantly co-expressed in the brain. A network of 66 genes was supported by ADHD-relevant phenotypes in the cross-species database. In addition, four significantly interconnected protein modules were found among the high-priority ADHD genes. A total of 26 genes were observed across all applied bioinformatic methods. Look-up in the latest genome-wide association study for ADHD showed that among those 26, POLR3C and RBFOX1 were also supported by common genetic variants.\n\nConclusionsIntegration of a stringent filtering procedure in CNV studies with suitable bioinformatics approaches can identify ADHD candidate genes at increased levels of credibility. Our pipeline provides additional insight in the molecular mechanisms underlying ADHD and allows prioritization of genes for functional validation in validated model organisms.

genetics↗

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

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

Shared genetic background between children and adults with attention deficit/hyperactivity disorder

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

genetics↗

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

Argonaute bypasses cellular obstacles without hindrance during target search

Argonaute (Ago) proteins are key players in gene regulation in eukaryotes and host defense in prokaryotes. For specific interference, Ago relies on base pairing between small nucleic acid guides and complementary target sequences. To efficiently scan nucleic acid chains for potential targets, Ago must bypass both secondary structures in mRNA and single stranded DNA as well as protein barriers. Through single-molecule FRET, we reveal that lateral diffusion is mediated mainly through protein-nucleic acid interactions, rather than interactions between the guide and targeted strand. This allows Ago to scan for targets with high efficiency but without maintaining tight contact with the DNA backbone. Real-time observations show that Ago "glides" short distances over secondary structures while using intersegmental jumps to reduce scanning redundancy and bypass protein barriers. Our single-molecule method in combination with kinetic analysis may serve as a novel platform to study the effect of sequence on search kinetics for other nucleic acid-guided proteins.

biophysics↗

bioRxiv2018

Dengue virus infection changes Aedes aegypti oviposition olfactory preferences

Aedes aegypti mosquitoes, main vectors for numerous flaviviruses, have olfactory preferences and are capable of olfactory learning especially when seeking their required environmental conditions to lay their eggs. In this study, we showed that semiochemical conditions during Aedes aegypti larval rearing affected future female choice for oviposition: water-reared mosquitoes preferred to lay eggs in water or p-cresol containers, while skatole reared mosquitoes preferred skatole sites. Using two independent behavioural assays, we showed that this skatole preference was lost in mosquitoes infected with dengue virus. Viral RNA was extracted from infected female mosquito heads, and an increase of virus load was detected from 3 to 10 days post infection, indicating replication in the insect head and possibly in the central nervous system. Expression of selected genes, potentially implied in olfactory learning processes, were also altered during dengue infection. Based on these results, we hypothesise that dengue virus infection alters gene expression in the mosquitos head and is associated with a loss of olfactory preferences, possibly modifying oviposition site choice of female mosquitoes.

animal behavior and cognition↗

bioRxiv2018

A cellular basis of human intelligence

It is generally assumed that human intelligence relies on efficient processing by neurons in our brain. Behavioral and brain-imaging studies robustly show that higher intelligence associates with faster reaction times and thicker gray matter in temporal and frontal cortical areas. However, no direct evidence exists that links individual neuron activity and structure to human intelligence. Since a large part of cortical grey matter consists of dendrites, these structures likely determine cortical architecture. In addition, dendrites strongly affect functional properties of neurons, including action potential speed. Thereby, dendritic size and action potential firing may constitute variation in cortical thickness, processing speed, and ultimately IQ.\n\nTo investigate this, we took advantage of brain tissue available from neurosurgery and recorded from pyramidal neurons in the medial temporal cortex, an area showing high association between cortical thickness, cortical activity and intelligence. Next, we reconstructed full dendritic structures of recorded neurons and combined these with brain-imaging data and IQ scores from the same subjects. We find that high IQ scores and large temporal cortical thickness associate with larger, more complex dendrites of human pyramidal neurons. We show in silico that larger dendrites enable pyramidal neurons to track activity of synaptic inputs with higher temporal precision, due to fast action potential initiation. Finally, we find that human pyramidal neurons of individuals with higher IQ scores sustain faster action potentials during repeated firing. These findings provide first evidence that human intelligence is associated with neuronal complexity, action potential speed and efficient information transfer in cortical neurons.

neuroscience↗

bioRxiv2017

Identification of genome-wide significant shared genomic segments in large extended Utah families at high risk for completed suicide

Suicide is the 10th leading cause of death in the US. While environment has undeniable impact, evidence suggests genetic factors play a significant role in completed suicide. We linked a resource of >4,500 DNA samples from completed suicides obtained from the Utah Medical Examiner to genealogical records and medical records data available on over 8 million individuals. This linking has resulted in the identification of high-risk extended families (7-9 generations) with significant familial risk of completed suicide. Familial aggregation across distant relatives minimizes effects of shared environment, provides more genetically homogeneous risk groups, and magnifies genetic risks through familial repetition. We analyzed Illumina PsychArray genotypes from suicide cases in 43 high-risk families, identifying 30 distinct shared genomic segments with genome-wide evidence (p=2.02E-07 to 1.30E-18) of segregation with completed suicide. The 207 genes implicated by the shared regions provide a focused set of genes for further study; 18 have been previously associated with suicide risk. While PsychArray variants do not represent exhaustive variation within the 207 genes, we investigated these for specific segregation within the high-risk families, and for association of variants with predicted functional impact in ~1300 additional Utah suicides unrelated to the discovery families. None of the limited PsychArray variants explained the high-risk family segregation; sequencing of these regions will be needed to discover segregating risk variants, which may be rarer or regulatory. However, additional association tests yielded four significant PsychArray variants (SP110, rs181058279; AGBL2, rs76215382; SUCLA2, rs121908538; APH1B, rs745918508), raising the likelihood that these genes confer risk of completed suicide.

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

The Kinetic Basis Of CRISPR-Cas Off-Targeting Rules

Cas nucleases are popular tools for genome editing applications due to their ability to introduce DNA breaks at desired genomic locations. Such differential targeting is achieved through loading an RNA guide complimentary to the intended target sequence. As it turns out, sequences with only a partial match to the guide can also be cleaved. A large number of experiments have shed light on this off-targeting, outlining a number of rather peculiar empirical rules that detail the effect of mismatches at various positions and at various relative distances. We construct a kinetic model predicting on-target cleavage efficiency as well as off-target specificity. Our model explains a unified targeting rule for any target harboring mismatches, independent of their abundance and placing, and the observed decoupling between efficiency and specificity when protein-DNA interactions are weakened. We favorably compare our model to published experimental data from CRISPR-Cas9, CRISPR-Cpf1, CRISPR-Cascade, as well as to the human Argonaute 2 systems. Understanding the origins of off-targeting principles is important for the further development of CRISPR-Cas as a precise genome editing tool.

biophysics↗