Characterizing Genetic Pathways Unique to Autism Spectrum Disorder at Multiple Levels of Biological Analysis.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by atypical patterns of social functioning and repetitive/restricted behaviors. ASD commonly co-occurs with ADHD and, despite their clinical distinctiveness, the two share considerable genetic overlap. Given their shared genetic liability, it is unclear which genetic pathways confer unique risk for ASD independent of ADHD. We applied Genomic Structural Equation Modeling (SEM) to GWAS summary statistics for ASD and ADHD, decomposing the genetic signal for ASD into that which is unique to ASD (uASD) and that which is shared with ADHD. We computed genetic correlations between uASD and 75 external traits to estimate genetic overlap between uASD and other clinically relevant phenotypes. We went on to apply Stratified Genomic SEM to identify classes of genes enriched for uASD. Finally, we implemented Transcriptome-Wide SEM (T-SEM) to explore patterns of gene-expression associated with uASD. We observed positive genetic correlations between uASD and several external traits, most notably those relating to cognitive/educational outcomes and internalizing psychiatric traits. Stratified Genomic SEM showed that heritability for uASD was significantly enriched in genes involved in evolutionarily conserved processes, as well as for a histone mark in the germinal matrix. T-SEM revealed 83 unique genes with expression associated with uASD, many of which were novel. These findings delineate the unique biological underpinnings of ASD which exist independent of ADHD and demonstrate the utility of Genomic SEM and its extensions for disambiguating shared and unique risk pathways for genetically overlapping traits.

Examining Differences in the Genetic and Functional Architecture of Attention-Deficit/Hyperactivity Disorder Diagnosed in Childhood and Adulthood.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with diagnostic criteria requiring symptoms to begin in childhood. We investigated whether individuals diagnosed as children differ from those diagnosed in adulthood with respect to shared and unique architecture at the genome-wide and gene expression level of analysis. Methods: We used genomic structural equation modeling (SEM) to investigate differences in genetic correlations (rg) of childhood-diagnosed (ncases = 14,878) and adulthood-diagnosed (ncases = 6961) ADHD with 98 behavioral, psychiatric, cognitive, and health outcomes. We went on to apply transcriptome-wide SEM to identify functional annotations and patterns of gene expression associated with genetic risk sharing or divergence across the ADHD subgroups. Results: Compared with the childhood subgroup, adulthood-diagnosed ADHD exhibited a significantly larger negative rg with educational attainment, the noncognitive skills of educational attainment, and age at first sexual intercourse. We observed a larger positive rg for adulthood-diagnosed ADHD with major depression, suicidal ideation, and a latent internalizing factor. At the gene expression level, transcriptome-wide SEM analyses revealed 22 genes that were significantly associated with shared genetic risk across the subtypes that reflected a mixture of coding and noncoding genes and included 15 novel genes relative to the ADHD subgroups. Conclusions: This study demonstrated that ADHD diagnosed later in life shows much stronger genetic overlap with internalizing disorders and related traits. This may indicate the potential clinical relevance of distinguishing these subgroups or increased misdiagnosis for those diagnosed later in life. Top transcriptome-wide SEM results implicated genes related to neuronal function and clinical characteristics (e.g., sleep).

It is unclear whether individuals who are diagnosed with attention-deficit/hyperactivity disorder (ADHD) as children differ from those who are diagnosed in adulthood with respect to their genetic architecture. We found that adulthood-diagnosed ADHD is much more genetically similar than ADHD diagnosed in childhood to disorders in the internalizing space, such as depression and suicidality. Differences between the distinct age groups at diagnosis highlight the importance of distinguishing these subgroups in a clinical and treatment setting.

Genomic SEM applied to explore etiological divergences in bipolar subtypes.

BACKGROUND: Bipolar disorder (BD) is an overarching diagnostic class defined by the presence of at least one prior manic episode (BD I) or both a prior hypomanic episode and a prior depressive episode (BD II). Traditionally, BD II has been conceptualized as a less severe presentation of BD I, however, extant literature to investigate this claim has been mixed. METHODS: We apply genomic structural equation modeling (Genomic SEM) to investigate divergent genetic pathways across BD's two major subtypes using the most recent GWAS summary statistics from the PGC. We begin by identifying divergences in genetic correlations across 98 external traits using a Bonferroni-corrected threshold. We also use a theoretically informed follow-up model to examine the extent to which the genetic variance in each subtype is explained by schizophrenia and major depression. Lastly, transcriptome-wide SEM (T-SEM) was used to identify neuronal gene expression patterns associated with BD subtypes. RESULTS: BD II was characterized by significantly larger genetic overlap across non-psychiatric medical and internalizing traits (e.g. heart disease, neuroticism, insomnia), while stronger associations for BD I were absent. Consistent with these findings, follow-up modeling revealed a substantial major depression component for BD II. T-SEM results revealed 35 unique genes associated with shared risk across BD subtypes. CONCLUSIONS: Divergent patterns of genetic relationships across external traits provide support for the distinction of the bipolar subtypes. However, our results also challenge the illness severity conceptualization of BD given stronger genetic overlap across BD II and a range of clinically relevant traits and disorders.

Quantum Key Distribution for Critical Infrastructures: Towards Cyber-Physical Security for Hydropower and Dams.

Hydropower facilities are often remotely monitored or controlled from a centralized remote control room. Additionally, major component manufacturers monitor the performance of installed components, increasingly via public communication infrastructures. While these communications enable efficiencies and increased reliability, they also expand the cyber-attack surface. Communications may use the internet to remote control a facility's control systems, or it may involve sending control commands over a network from a control room to a machine. The content could be encrypted and decrypted using a public key to protect the communicated information. These cryptographic encoding and decoding schemes become vulnerable as more advances are made in computer technologies, such as quantum computing. In contrast, quantum key distribution (QKD) and other quantum cryptographic protocols are not based upon a computational problem, and offer an alternative to symmetric cryptography in some scenarios. Although the underlying mechanism of quantum cryptogrpahic protocols such as QKD ensure that any attempt by an adversary to observe the quantum part of the protocol will result in a detectable signature as an increased error rate, potentially even preventing key generation, it serves as a warning for further investigation. In QKD, when the error rate is low enough and enough photons have been detected, a shared private key can be generated known only to the sender and receiver. We describe how this novel technology and its several modalities could benefit the critical infrastructures of dams or hydropower facilities. The presented discussions may be viewed as a precursor to a quantum cybersecurity roadmap for the identification of relevant threats and mitigation.

Genomic SEM Applied to Explore Etiological Divergences in Bipolar Subtypes.

Background: Bipolar Disorder (BD) is an overarching diagnostic class defined by the presence of at least one prior manic episode (BD I) or both a prior hypomanic episode and a prior depressive episode (BD II). Traditionally, BD II has been conceptualized as a less severe presentation of BD I, however, extant literature to investigate this claim has been mixed. Methods: We apply Genomic Structural Equation Modeling (Genomic SEM) to investigate divergent genetic pathways across BD's two major subtypes using the most recent GWAS summary statistics from the PGC. We begin by identifying divergences in genetic correlations across 89 external traits using a Bonferroni corrected threshold. We also use a theoretically informed follow-up model to examine the extent to which the genetic variance in each subtype is explained by schizophrenia and major depression. Lastly, Transcriptome-wide SEM (T-SEM) was used to identify gene expression patterns associated with the BD subtypes. Results: BD II was characterized by significantly larger genetic overlap with internalizing traits (e.g., neuroticism, insomnia, physical inactivity), while significantly stronger associations for BD I were limited. Consistent with these findings, the follow-up model revealed a much larger major depression component for BD II. T-SEM results revealed 41 unique genes associated with risk pathways across BD subtypes. Conclusions: Divergent patterns of genetic relationships across external traits provide support for the distinction of the bipolar subtypes. However, our results also challenge the illness severity conceptualization of BD given stronger genetic overlap across BD II and a range of clinically relevant traits and disorders.

Update on Treatment Options for Advanced Bile Duct Tumours: Radioembolisation for Advanced Cholangiocarcinoma.

Cholangiocarcinoma is a rare form of gastrointestinal cancer with a poor prognosis. Patients often present with biliary obstruction or non-specific abdominal pain, and a high proportion of patients have advanced disease at initial diagnosis. The goal of this review is to discuss treatment options for patients with advanced bile duct tumours focusing on radioembolisation (RE) and its impact on overall survival. RE provides a therapeutic option for patients with unresectable cholangiocarcinoma. However, although systemic chemotherapy has demonstrated a survival benefit in randomised controlled trials, there is limited supporting evidence for the use of RE in this setting. Studies are mostly limited to single-centre, small cohorts with variable outcome measures. Additionally, patients included in these studies received a variety of previous therapies including chemotherapy, surgery or alternative intra-arterial therapy; therefore, a true assessment of overall survival benefit is difficult.