03022nas a2200481 4500008004100000022001400041245011800055210006900173260001300242300001000255490000600265520167500271653001001946653002201956653001201978653002101990653004002011653001102051653001402062653002802076653001102104653000902115653001302124100001302137700002102150700001702171700002902188700002202217700001902239700002302258700002102281700002402302700002102326700002402347700001902371700001902390700002102409700002002430700001902450700001402469700002102483856003602504 2015 eng d a1942-326800aAssociation of Rare Loss-Of-Function Alleles in HAL, Serum Histidine: Levels and Incident Coronary Heart Disease.0 aAssociation of Rare LossOfFunction Alleles in HAL Serum Histidin c2015 Apr a351-50 v83 a

BACKGROUND: Histidine is a semiessential amino acid with antioxidant and anti-inflammatory properties. Few data are available on the associations between genetic variants, histidine levels, and incident coronary heart disease (CHD) in a population-based sample.

METHODS AND RESULTS: By conducting whole exome sequencing on 1152 African Americans in the Atherosclerosis Risk in Communities (ARIC) study and focusing on loss-of-function (LoF) variants, we identified 3 novel rare LoF variants in HAL, a gene that encodes histidine ammonia-lyase in the first step of histidine catabolism. These LoF variants had large effects on blood histidine levels (β=0.26; P=1.2×10(-13)). The positive association with histidine levels was replicated by genotyping an independent sample of 718 ARIC African Americans (minor allele frequency=1%; P=1.2×10(-4)). In addition, high blood histidine levels were associated with reduced risk of developing incident CHD with an average of 21.5 years of follow-up among African Americans (hazard ratio=0.18; P=1.9×10(-4)). This finding was validated in an independent sample of European Americans from the Framingham Heart Study (FHS) Offspring Cohort. However, LoF variants in HAL were not directly significantly associated with incident CHD after meta-analyzing results from the CHARGE Consortium.

CONCLUSIONS: Three LoF mutations in HAL were associated with increased histidine levels, which in turn were shown to be inversely related to the risk of CHD among both African Americans and European Americans. Future investigations on the association between HAL gene variation and CHD are warranted.

10aAdult10aAfrican Americans10aAlleles10aCoronary Disease10aEuropean Continental Ancestry Group10aFemale10aHistidine10aHistidine Ammonia-Lyase10aHumans10aMale10aMutation1 aYu, Bing1 aLi, Alexander, H1 aMuzny, Donna1 aVeeraraghavan, Narayanan1 ade Vries, Paul, S1 aBis, Joshua, C1 aMusani, Solomon, K1 aAlexander, Danny1 aMorrison, Alanna, C1 aFranco, Oscar, H1 aUitterlinden, Andre1 aHofman, Albert1 aDehghan, Abbas1 aWilson, James, G1 aPsaty, Bruce, M1 aGibbs, Richard1 aWei, Peng1 aBoerwinkle, Eric uhttps://chs-nhlbi.org/node/668903088nas a2200289 4500008004100000022001400041245008600055210006900141260001600210300000800226490000700234520224200241653002302483653001802506653001302524653004202537653001102579100001802590700001902608700002902627700002002656700001902676700002102695700003302716700001302749856003602762 2016 eng d a1471-210500aA hybrid computational strategy to address WGS variant analysis in >5000 samples.0 ahybrid computational strategy to address WGS variant analysis in c2016 Sep 10 a3610 v173 a

BACKGROUND: The decreasing costs of sequencing are driving the need for cost effective and real time variant calling of whole genome sequencing data. The scale of these projects are far beyond the capacity of typical computing resources available with most research labs. Other infrastructures like the cloud AWS environment and supercomputers also have limitations due to which large scale joint variant calling becomes infeasible, and infrastructure specific variant calling strategies either fail to scale up to large datasets or abandon joint calling strategies.

RESULTS: We present a high throughput framework including multiple variant callers for single nucleotide variant (SNV) calling, which leverages hybrid computing infrastructure consisting of cloud AWS, supercomputers and local high performance computing infrastructures. We present a novel binning approach for large scale joint variant calling and imputation which can scale up to over 10,000 samples while producing SNV callsets with high sensitivity and specificity. As a proof of principle, we present results of analysis on Cohorts for Heart And Aging Research in Genomic Epidemiology (CHARGE) WGS freeze 3 dataset in which joint calling, imputation and phasing of over 5300 whole genome samples was produced in under 6 weeks using four state-of-the-art callers. The callers used were SNPTools, GATK-HaplotypeCaller, GATK-UnifiedGenotyper and GotCloud. We used Amazon AWS, a 4000-core in-house cluster at Baylor College of Medicine, IBM power PC Blue BioU at Rice and Rhea at Oak Ridge National Laboratory (ORNL) for the computation. AWS was used for joint calling of 180 TB of BAM files, and ORNL and Rice supercomputers were used for the imputation and phasing step. All other steps were carried out on the local compute cluster. The entire operation used 5.2 million core hours and only transferred a total of 6 TB of data across the platforms.

CONCLUSIONS: Even with increasing sizes of whole genome datasets, ensemble joint calling of SNVs for low coverage data can be accomplished in a scalable, cost effective and fast manner by using heterogeneous computing platforms without compromising on the quality of variants.

10aDatabases, Genetic10aGenome, Human10aGenomics10aHigh-Throughput Nucleotide Sequencing10aHumans1 aHuang, Zhuoyi1 aRustagi, Navin1 aVeeraraghavan, Narayanan1 aCarroll, Andrew1 aGibbs, Richard1 aBoerwinkle, Eric1 aVenkata, Manjunath, Gorentla1 aYu, Fuli uhttps://chs-nhlbi.org/node/8564