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.

The majority of variants identified by genome--wide association studies (GWAS) reside in the noncoding genome, where they affect regulatory elements including transcriptional enhancers.We propose INFERNO (INFERring the molecular mechanisms of NOncoding genetic variants), a novel method which integrates hundreds of diverse functional genomics data sources with GWAS summary statistics to identify putatively causal noncoding variants underlying association signals. INFERNO comprehensively infers the relevant tissue contexts, target genes, and downstream biological processes affected by causal variants. We apply INFERNO to schizophrenia GWAS data, recapitulating known schizophrenia--associated genes including CACNA1C and discovering novel signals related to transmembrane cellular processes.

Kernel-based approaches for sequence classification have been successfully applied to a variety of domains, including the text categorization, image classification, speech analysis, biological sequence analysis, time series and music classification, where they show some of the most accurate results.Typical kernel functions for sequences in these domains (e.g., bag-of-words, mismatch, or subsequence kernels) are restricted to discrete univariate (i.e. one-dimensional) string data, such as sequences of words in the text analysis, codeword sequences in the image analysis, or nucleotide or amino acid sequences in the DNA and protein sequence analysis. However, original sequence data are often of real-valued multivariate nature, i.e. are not univariate and discrete as required by typical k-mer based sequence kernel functions.In this work, we consider the problem of the multivariate sequence classification (e.g., classification of multivariate music sequences, or multidimensional protein sequence representations). To this end, we extend univariate kernel functions typically used in sequence domains and propose efficient multivariate similarity kernel method (MVDFQ-SK) based on (1) a direct feature quantization (DFQ) of each sequence dimension in the original real-valued multivariate sequences and (2) applying novel multivariate discrete kernel measures on these multivariate discrete DFQ sequence representations to more accurately capture similarity relationships among sequences and improve classification performance.Experiments using the proposed MVDFQ-SK kernel method show excellent classification performance on three challenging music classification tasks as well as protein sequence classification with significant 25-40% improvements over univariate kernel methods and existing state-of-the-art sequence classification methods.

INTRODUCTIONThe NIAGADS Alzheimer’s Genomics Database is an interactive knowledgebase for AD genetics that provides access to GWAS summary statistics datasets deposited at NIAGADS, a national genetics data repository for AD and related dementia (ADRD).METHODSThe website makes available >70 genome-wide summary statistics datasets from GWAS and genome sequencing analysis for AD/ADRD. Variants identified from these datasets are mapped to up-to-date variant and gene annotations from a variety of resources and linked to functional genomics data.The database is powered by a big-data optimized relational database and ontologies to consistently annotate study designs and phenotypes, facilitating data harmonization and efficient real-time data analysis and variant or gene report generation.RESULTSDetailed variant reports provide tabular and interactive graphical summaries of known ADRD associations, as well as highlight variants flagged by the Alzheimer’s Disease Sequencing Project (ADSP). Gene reports provide summaries of co-located ADRD risk-associated variants and have been expanded to include meta-analysis results from aggregate association tests performed by the ADSP allowing us to flag genes with genetic-evidence for AD.DISCUSSIONThe GenomicsDB makes available >100 million variant annotations, including ~30 million (5 million novel) variants identified as AD-relevant by ADSP, for browsing and real-time mining via the website or programmatically through a REST API. With a newly redesigned, efficient, search interface and comprehensive record pages linking summary statistics to variant and gene annotations, this resource makes these data both accessible and interpretable, establishing itself as valuable tool for AD research.

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