Fast and Rigorous Computation of Gene and Pathway Scores from SNP-Based Summary Statistics

PLoS Computational Biology
David LamparterSven Bergmann

Abstract

Integrating single nucleotide polymorphism (SNP) p-values from genome-wide association studies (GWAS) across genes and pathways is a strategy to improve statistical power and gain biological insight. Here, we present Pascal (Pathway scoring algorithm), a powerful tool for computing gene and pathway scores from SNP-phenotype association summary statistics. For gene score computation, we implemented analytic and efficient numerical solutions to calculate test statistics. We examined in particular the sum and the maximum of chi-squared statistics, which measure the strongest and the average association signals per gene, respectively. For pathway scoring, we use a modified Fisher method, which offers not only significant power improvement over more traditional enrichment strategies, but also eliminates the problem of arbitrary threshold selection inherent in any binary membership based pathway enrichment approach. We demonstrate the marked increase in power by analyzing summary statistics from dozens of large meta-studies for various traits. Our extensive testing indicates that our method not only excels in rigorous type I error control, but also results in more biologically meaningful discoveries.

References

Dec 10, 1998·Nucleic Acids Research·H OgataM Kanehisa
Sep 4, 2003·Genome Research·Paul D ThomasApurva Narechania
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Jun 8, 2007·Nature·UNKNOWN Wellcome Trust Case Control Consortium
Oct 30, 2007·American Journal of Human Genetics·Kai WangMaja Bucan
Oct 30, 2007·American Journal of Human Genetics·Karen N Conneely, Michael Boehnke
Mar 20, 2008·The Journal of Bone and Joint Surgery. American Volume·Timothy F Day, Yingzi Yang
Jun 23, 2009·American Journal of Human Genetics·Peter HolmansNick Craddock
Nov 17, 2009·Nature Genetics·Marcin ImielinskiHakon Hakonarson
Apr 27, 2010·Nature Genetics·UNKNOWN Tobacco and Genetics Consortium
Jul 6, 2010·American Journal of Human Genetics·Jimmy Z LiuStuart Macgregor
Sep 3, 2010·Nature·UNKNOWN International HapMap 3 ConsortiumJean E McEwen
Nov 12, 2010·Nucleic Acids Research·David CroftLincoln Stein
Mar 15, 2011·American Journal of Human Genetics·Miao-Xin LiPak C Sham
Jul 9, 2011·American Journal of Human Genetics·Michael C WuXihong Lin
Aug 9, 2011·Journal of Lipids·Katayoon B Ebrahimi, James T Handa
Jan 17, 2012·American Journal of Human Genetics·Peter M VisscherJian Yang
Nov 6, 2012·American Journal of Human Genetics·Georg B EhretZoltán Kutalik
Nov 7, 2012·Nature·UNKNOWN 1000 Genomes Project ConsortiumGil A McVean
Oct 8, 2013·Nature Genetics·Cristen J WillerUNKNOWN Global Lipids Genetics Consortium
Nov 12, 2013·Nucleic Acids Research·Minoru KanehisaMao Tanabe
Dec 25, 2013·Frontiers in Genetics·Lin Hou, Hongyu Zhao
Jan 7, 2014·Nature·Yukinori OkadaRobert M Plenge
Dec 17, 2014·Bioinformatics·Donghyung LeeSilviu-Alin Bacanu
Dec 19, 2014·Twin Research and Human Genetics : the Official Journal of the International Society for Twin Studies·Aniket Mishra, Stuart Macgregor

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Citations

Jul 28, 2016·Schizophrenia Bulletin·Yong WuXiong-Jian Luo
Sep 3, 2016·Bioinformatics·Sungyoung LeeTaesung Park
Mar 8, 2017·Biological Psychiatry·Carolien G F de KovelClyde Francks
Jul 28, 2017·Nature Communications·Aaron F McDaidZoltán Kutalik
Mar 14, 2018·Genetic Epidemiology·Emily BakerWith The Gerad Consortium
Mar 27, 2018·Bioinformatics·Claudia GiambartolomeiPanos Roussos
Apr 5, 2018·PloS One·Dalton ConleyMark L Siegal
Oct 5, 2017·Molecular BioSystems·Wenran LiRui Jiang
Dec 1, 2017·Nature Communications·Kyoko WatanabeDanielle Posthuma
Oct 11, 2017·Nature Reviews. Genetics·Sujoy Ghosh, Claude Bouchard
Jan 27, 2019·Annals of the Rheumatic Diseases·Shuji AkizukiChikashi Terao
Apr 13, 2017·European Journal of Human Genetics : EJHG·Shonosuke SugasawaShigeyuki Matsui
Apr 17, 2019·Annals of Neurology·Jessica SchulzChristina M Lill
Jul 4, 2019·PLoS Computational Biology·Andrea KomljenovicMarc Robinson-Rechavi
Sep 3, 2019·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Ikuo OtsukaAkitoyo Hishimoto
Nov 5, 2019·Nucleic Acids Research·Peilin JiaZhongming Zhao
Sep 10, 2019·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Petros TakousisLars Bertram
Sep 29, 2019·Nature Communications·Masato AkiyamaYoichiro Kamatani
Apr 15, 2020·PLoS Computational Biology·Olga A VsevolozhskayaDmitri V Zaykin
Sep 1, 2019·Nature Methods·Sarvenaz ChoobdarDaniel Marbach
Apr 10, 2020·Bioinformatics·Mattia TomasoniSven Bergmann
Jun 28, 2020·Brain : a Journal of Neurology·Chun Chieh FanAnders M Dale
Nov 8, 2018·Database : the Journal of Biological Databases and Curation·Ruifeng HuZhongming Zhao
Mar 13, 2019·Bioinformatics·Gulnara R SvishchevaTatiana I Axenovich
Apr 14, 2019·Scientific Reports·Carolien G F de Kovel, Clyde Francks
Aug 27, 2019·Frontiers in Genetics·Aitana Alonso-GonzalezAngel Carracedo
Nov 20, 2019·Nature Communications·Karla MisselbeckCorrado Priami
Jan 22, 2020·Nature Human Behaviour·Nana MatobaYukinori Okada

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Software Mentioned

Versatile Gene - based Association Study ( VEGAS )
VEGAS
thway sc oring al gorithm
BIOCARTA
CoLaus
KEGG
PANTHER
Pascal
Pascal pipeline
MAGENTA

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