Biology subjects

Vardarajan, B. N.

Publications and source records attributed to Vardarajan, B. N..

3 recordsLinked to original sources

bioRxiv2018

Quality Control and Integration of Genotypes from Two Calling Pipelines for Whole Genome Sequence Data in the Alzheimer’s Disease Sequencing Project

The Alzheimers Disease Sequencing Project (ADSP) performed whole genome sequencing (WGS) of 584 subjects from 111 multiplex families at three sequencing centers. Genotype calling of single nucleotide variants (SNVs) and insertion-deletion variants (indels) was performed centrally using GATK-HaplotypeCaller and Atlas V2. The ADSP Quality Control (QC) Working Group applied QC protocols to project-level variant call format files (VCFs) from each pipeline, and developed and implemented a novel protocol, termed \"consensus calling,\" to combine genotype calls from both pipelines into a single high-quality set. QC was applied to autosomal bi-allelic SNVs and indels, and included pipeline-recommended QC filters, variant-level QC, and sample-level QC. Low-quality variants or genotypes were excluded, and sample outliers were noted. Quality was assessed by examining Mendelian inconsistencies (MIs) among 67 parent-offspring pairs, and MIs were used to establish additional genotype-specific filters for GATK calls. After QC, 578 subjects remained. Pipeline-specific QC excluded ~12.0% of GATK and 14.5% of Atlas SNVs. Between pipelines, ~91% of SNV genotypes across all QCed variants were concordant; 4.23% and 4.56% of genotypes were exclusive to Atlas or GATK, respectively; the remaining ~0.01% of discordant genotypes were excluded. For indels, variant-level QC excluded ~36.8% of GATK and 35.3% of Atlas indels. Between pipelines, ~55.6% of indel genotypes were concordant; while 10.3% and 28.3% were exclusive to Atlas or GATK, respectively; and ~0.29% of discordant genotypes were. The final WGS consensus dataset contains 27,896,774 SNVs and 3,133,926 indels and is publicly available.\n\nAbbreviationsAD, Alzheimers disease; QC, Quality Control; LSSAC, Large-Scale Sequencing and Analysis Center; Broad, Broad Institute Genomics Service; Baylor, Baylor College of Medicine Human Genome Sequencing Center; WashU, Washington University-St. Louis McDonnell Genome Institute; WGS, whole genome sequencing; WES, whole exome sequencing; indel, insertion-deletion variants; VCF, variant control format; MI, Mendelian inconsistency; MC, Mendelian consistency; GWAS, genome-wide association study; VR, referent allele read depth; DP, overall read depth; MS, mapping score; GQ, genotype quality score; Ti/Tv, Transition/Transversion; CS, concordance code

genetics↗

bioRxiv2018

Whole Exome Sequencing in 20,197 Persons for Rare Variants in Alzheimer Disease

ObjectiveThe genetic bases of Alzheimers disease remain uncertain. An international effort to fully articulate genetic risks and protective factors is underway with the hope of identifying potential therapeutic targets and preventive strategies. The goal here was to identify and characterize the frequency and impact of rare and ultra-rare variants in Alzheimers disease using whole exome sequencing in 20,197 individuals.\n\nMethodsWe used a gene-based collapsing analysis of loss-of-function ultra-rare variants in a case-control study design with data from the Washington Heights-Inwood Columbia Aging Project, the Alzheimers Disease Sequencing Project and unrelated individuals from the Institute of Genomic Medicine at Columbia University.\n\nResultsWe identified 19 cases carrying extremely rare SORL1 loss-of-function variants among a collection of 6,965 cases and a single loss-of-function variant among 13,252 controls (p = 2.17 x 10-8; OR 36.2 [95%CI 5.8 - 1493.0]). Age-at-onset was seven years earlier for patients with SORL1 qualifying variant compared with non-carriers. No other gene attained a study-wide level of statistical significance, but multiple top-ranked genes, including GRID2IP, WDR76 and GRN, were among candidates for follow-up studies.\n\nInterpretationThis study implicates ultra-rare, loss-of-function variants in SORL1 as a significant genetic risk factor for Alzheimers disease and provides a comprehensive dataset comparing the burden of rare variation in nearly all human genes in Alzheimers disease cases and controls. This is the first investigation to establish a genome-wide statistically significant association between multiple extremely rare loss-of-function variants in SORL1 and Alzheimers disease in a large whole-exome study of unrelated cases and controls.

genetics↗

bioRxiv2018

A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research

We initiated the systematic profiling of the dorsolateral prefrontal cortex obtained from a subset of autopsied individuals enrolled in the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP), which are jointly designed and belong to a very few prospective studies of aging and dementia with detailed, longitudinal cognitive phenotyping during life and a quantitative, structured neuropathologic examination after death for >3,322 subjects. Here, we outline the first generation of data including genome-wide genotypes (n=2,090), whole genome sequencing (n=1,179), DNA methylation (n=740), chromatin immunoprecipitation with sequencing using an anti-Histone 3 Lysine 9 acetylation (H3K9Ac) antibody (n=712), RNA sequencing (n=638), and miRNA profile (n=702). Generation of other omic data including ATACseq, proteomic and metabolomics profiles is ongoing. Thanks to its prospective design and recruitment of older, non-demented individuals, these data can be repurposed to investigate a large number of syndromic and quantitative neuroscience phenotypes. The many subjects that are cognitively non-impaired at death also offer insights into the biology of the human brain in older non-impaired individuals.

cell biology↗