ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Phytochrome-mediated photoperception and signal transduction in higher plants

Light provides a major source of information from the environment during plant growth and development. Light perception is mediated through the action of several photoreceptors, including the phytochromes. Recent results demonstrate that light responses involve the regulation of several thousand genes. Some of the key events controlling this gene expression are the translocation of the phytochrome photoreceptors into the nucleus followed by their binding to transcription factors. Coupled with these events, the degradation of positively acting intermediates appears to be an important process whereby photomorphogenesis is repressed in darkness. This review summarizes our current knowledge of these processes

Overexpression of LSH1, a member of an uncharacterised gene family, causes enhanced light regulation of seedling development

Light regulates plant growth and development through a network of endogenous factors. By screening Arabidopsis activation-tagged lines, we isolated a dominant mutant (light-dependent short hypocotyls 1-D (Ish1-D)) that showed hypersensitive responses to continuous red (cR), far-red (cFR) and blue (cB) light and cloned the corresponding gene, LSH1. LSH1 encodes a nuclear protein of a novel gene family that has homologues in Arabidopsis and rice. The effects of the Ish1-D mutation were tested in a series of photoreceptor mutant backgrounds. The hypersensitivity to cFR and cB light conferred by Ish1-D was abolished in a phyA null background (phyA-201), and the hypersensitivity to cR and cFR light conferred by Ish1-D was much reduced in the phytochrome- chromophore synthetic mutant, hy1-1 (long hypocotyl 1). These results indicate that LSH1 is functionally dependent on phytochrome to mediate light regulation of seedling development.Peer reviewe