Genetics of Alzheimer's disease: recent advances

Alzheimer's disease is a progressive neurodegenerative disorder with high prevalence in old age. It is the most common cause of dementia, with a risk reaching 50% after the age of 85 years, and with the increasing age of the population it is one of the biggest healthcare challenges of the 21st century. Genetic variation is an important contributor to the risk for this disease, underlying an estimated heritability of about 70%. Alzheimer's genetics research in the 1990s was successful in identifying three genes accounting for most cases of early-onset disease with autosomal dominant inheritance, and one gene involved in the more common late-onset disease, which shows complex inheritance patterns. Despite the presence of significant remaining genetic contribution to the risk, the identification of genes since then has been elusive, reminiscent of most other complex disorders. In the past decade there have been significant efforts towards a systematic evaluation of the multiple genetic association studies for Alzheimer's disease, while the first genome-wide association studies are now being reported with promising results. As sample sizes grow through new collections and collaborative efforts, and as new technologies make it possible to test alternative hypotheses, it is expected that new genes involved in the disease will soon be identified and confirmed. The gene discoveries of the 1990s have taught us a lot about Alzheimer's disease pathogenesis, providing many therapeutic targets that are currently at various stages of testing for future clinical use. As new genes become known and the biological pathways leading to disease are further explored, the possibility of prevention and successful personalized treatment is becoming tangible, providing hope for the millions of patients with Alzheimer's disease and their caregivers

Photonic integration enabling new multiplexing concepts in optical board-to-board and rack-to-rack interconnects

New broadband applications are causing the datacenters to proliferate, raising the bar for higher interconnection speeds. So far, optical board-to-board and rack-to-rack interconnects relied primarily on low-cost commodity optical components assembled in a single package. Although this concept proved successful in the first generations of optical-interconnect modules, scalability is a daunting issue as signaling rates extend beyond 25 Gb/s. In this paper we present our work towards the development of two technology platforms for migration beyond Infiniband enhanced data rate (EDR), introducing new concepts in board-to-board and rack-to-rack interconnects. The first platform is developed in the framework of MIRAGE European project and relies on proven VCSEL technology, exploiting the inherent cost, yield, reliability and power consumption advantages of VCSELs. Wavelength multiplexing, PAM-4 modulation and multi-core fiber (MCF) multiplexing are introduced by combining VCSELs with integrated Si and glass photonics as well as BiCMOS electronics. An in-plane MCF-to-SOI interface is demonstrated, allowing coupling from the MCF cores to 340x400 nm Si waveguides. Development of a low-power VCSEL driver with integrated feed-forward equalizer is reported, allowing PAM-4 modulation of a bandwidth-limited VCSEL beyond 25 Gbaud. The second platform, developed within the frames of the European project PHOXTROT, considers the use of modulation formats of increased complexity in the context of optical interconnects. Powered by the evolution of DSP technology and towards an integration path between inter and intra datacenter traffic, this platform investigates optical interconnection system concepts capable to support 16QAM 40GBd data traffic, exploiting the advancements of silicon and polymer technologies

Photonic Provisioning Using a Packaged SOI Hybrid All-Optical Wavelength Converter in a Meshed Optical Network Testbed

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Chapter Merging Plasmonics and Silicon Photonics Towards Greener and Faster “Network-on-Chip” Solutions for Data Centers and High-Performance Computing Systems

Endocrinolog

Merging Plasmonics and Silicon Photonics Towards Greener and Faster “Network-on-Chip” Solutions for Data Centers and High-Performance Computing Systems

Endocrinolog

Whole-Genome Sequencing of a Single Proband Together with Linkage Analysis Identifies a Mendelian Disease Gene

Although more than 2,400 genes have been shown to contain variants that cause Mendelian disease, there are still several thousand such diseases yet to be molecularly defined. The ability of new whole-genome sequencing technologies to rapidly indentify most of the genetic variants in any given genome opens an exciting opportunity to identify these disease genes. Here we sequenced the whole genome of a single patient with the dominant Mendelian disease, metachondromatosis (OMIM 156250), and used partial linkage data from her small family to focus our search for the responsible variant. In the proband, we identified an 11 bp deletion in exon four of PTPN11, which alters frame, results in premature translation termination, and co-segregates with the phenotype. In a second metachondromatosis family, we confirmed our result by identifying a nonsense mutation in exon 4 of PTPN11 that also co-segregates with the phenotype. Sequencing PTPN11 exon 4 in 469 controls showed no such protein truncating variants, supporting the pathogenicity of these two mutations. This combination of a new technology and a classical genetic approach provides a powerful strategy to discover the genes responsible for unexplained Mendelian disorders

Glutathione pathway gene variation and risk of autism spectrum disorders

Despite evidence that autism is highly heritable with estimates of 15 or more genes involved, few studies have directly examined associations of multiple gene interactions. Since inability to effectively combat oxidative stress has been suggested as a mechanism of autism, we examined genetic variation 42 genes (308 single-nucleotide polymorphisms (SNPs)) related to glutathione, the most important antioxidant in the brain, for both marginal association and multi-gene interaction among 318 case–parent trios from The Autism Genetic Resource Exchange. Models of multi-SNP interactions were estimated using the trio Logic Regression method. A three-SNP joint effect was observed for genotype combinations of SNPs in glutaredoxin, glutaredoxin 3 (GLRX3), and cystathione gamma lyase (CTH); OR = 3.78, 95% CI: 2.36, 6.04. Marginal associations were observed for four genes including two involved in the three-way interaction: CTH, alcohol dehydrogenase 5, gamma-glutamylcysteine synthetase, catalytic subunit and GLRX3. These results suggest that variation in genes involved in counterbalancing oxidative stress may contribute to autism, though replication is necessary

Pleiotropic meta-analysis of cognition, education, and schizophrenia differentiates roles of early neurodevelopmental and adult synaptic pathways

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected (“concordant”) direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive (“discordant”) relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10−8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms—early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways—that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.Peer reviewe

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Intelligence is highly heritable(1) and a major determinant of human health and well-being(2). Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.Peer reviewe