Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types

Nature Genetics
Hilary K FinucaneAlkes L Price

Abstract

We introduce an approach to identify disease-relevant tissues and cell types by analyzing gene expression data together with genome-wide association study (GWAS) summary statistics. Our approach uses stratified linkage disequilibrium (LD) score regression to test whether disease heritability is enriched in regions surrounding genes with the highest specific expression in a given tissue. We applied our approach to gene expression data from several sources together with GWAS summary statistics for 48 diseases and traits (average N = 169,331) and found significant tissue-specific enrichments (false discovery rate (FDR) < 5%) for 34 traits. In our analysis of multiple tissues, we detected a broad range of enrichments that recapitulated known biology. In our brain-specific analysis, significant enrichments included an enrichment of inhibitory over excitatory neurons for bipolar disorder, and excitatory over inhibitory neurons for schizophrenia and body mass index. Our results demonstrate that our polygenic approach is a powerful way to leverage gene expression data for interpreting GWAS signals.

References

May 30, 2001·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·F M Benes, S Berretta
Jan 31, 2002·Annual Review of Medicine·Timothy E WilensThomas J Spencer
Feb 6, 2003·The Journal of Clinical Investigation·Weijun JinDaniel J Rader
May 1, 2004·Circulation Research·Uli C BroedlDaniel J Rader
Mar 11, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Suzana Herculano-Houzel, Roberto Lent
Mar 18, 2005·Annual Review of Immunology·Mireia Sospedra, Roland Martin
Aug 26, 2006·Nature Clinical Practice. Rheumatology·Ulf Müller-LadnerSteffen Gay
Dec 15, 2006·Nature·Gökhan S Hotamisligil
Apr 14, 2007·Science·James C LoYang-Xin Fu
Jul 27, 2007·Nature·Ramnik J Xavier, D K Podolsky
Dec 12, 2007·Neuropathology : Official Journal of the Japanese Society of Neuropathology·Tsutomu SakaiMasahiko Mikuni
Jan 4, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·John D CahoyBen A Barres
Sep 19, 2008·Nature Immunology·Tracy S P HengImmunological Genome Project Consortium
Jan 29, 2010·European Archives of Psychiatry and Clinical Neuroscience·Johann SteinerBernhard Bogerts
Mar 2, 2010·Nature Genetics·Patrick C A DuboisDavid A van Heel
Aug 6, 2010·Nature·Tanya M TeslovichSekar Kathiresan
Oct 15, 2010·Journal of Lipid Research·Kenneth R Feingold, Carl Grunfeld
Nov 10, 2010·Nature Reviews. Immunology·Clare M Lloyd, Edith M Hessel
Jan 29, 2011·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Amy DhirapongM Eric Gershwin
Mar 29, 2011·Nature·Jason ErnstBradley E Bernstein
Sep 23, 2011·Molecular Pain·Nasim MalekiDavid Borsook
Oct 4, 2011·American Journal of Human Genetics·Xinli HuSoumya Raychaudhuri
Oct 8, 2011·PLoS Genetics·Jonathan P BradfieldHakon Hakonarson
Dec 23, 2011·Annals of Neurology·Nikolaos A PatsopoulosPaul I W de Bakker
Aug 9, 2012·Theory in Biosciences = Theorie in Den Biowissenschaften·Günter P WagnerVincent J Lynch
Sep 8, 2012·Nature·ENCODE Project Consortium
Sep 8, 2012·Science·Matthew T MauranoJohn Stamatoyannopoulos
Dec 25, 2012·Nature Genetics·Gosia TrynkaSoumya Raychaudhuri
Aug 3, 2013·The Australian and New Zealand Journal of Psychiatry·Sanil Rege, Suzanne J Hodgkinson
Aug 13, 2013·Nature Genetics·Cross-Disorder Group of the Psychiatric Genomics ConsortiumInternational Inflammatory Bowel Disease Genetics Consortium (IIBDGC)
Jan 7, 2014·Nature·Yukinori OkadaRobert M Plenge
Feb 4, 2014·Genome Biology·Charity W LawGordon K Smyth
Feb 22, 2014·Neuroimmunomodulation·Izabela Guimarães BarbosaAntonio L Teixeira
Mar 25, 2014·American Journal of Human Genetics·Daniel WooInternational Stroke Genetics Consortium
Apr 8, 2014·American Journal of Human Genetics·Joseph K Pickrell
May 13, 2014·Bioinformatics·Kamil SlowikowskiSoumya Raychaudhuri
Jul 22, 2014·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Jun ZhangM Eric Gershwin
Jul 25, 2014·Nature·Schizophrenia Working Group of the Psychiatric Genomics Consortium
Aug 5, 2014·Lancet Neurology·International League Against Epilepsy Consortium on Complex Epilepsies. Electronic address: epilepsy-austin@unimelb.edu.au
Nov 5, 2014·Nature·Kyle FarhBradley E Bernstein
Dec 3, 2014·American Journal of Human Genetics·Alexander GusevSWE-SCZ Consortium
Jan 13, 2015·Nature Genetics·Rudolf S N FehrmannLude Franke
Feb 3, 2015·Nature Genetics·Brendan Bulik-SullivanBenjamin M Neale
Feb 20, 2015·Nature·Roadmap Epigenomics ConsortiumManolis Kellis
Oct 4, 2015·Nature·1000 Genomes Project ConsortiumGoncalo Abecasis
Nov 26, 2015·Nature Neuroscience·PsychENCODE ConsortiumNenad Sestan
Jan 28, 2016·Nature·Aswin SekarSteven A McCarroll
Feb 7, 2016·Bipolar Disorders·Lindsay C HanfordRoberto B Sassi
Feb 9, 2016·Nature Genetics·Alexander GusevBogdan Pasaniuc
Apr 20, 2016·International Journal of Obesity : Journal of the International Association for the Study of Obesity·N MedicP C Fletcher
Jun 21, 2016·Nature Genetics·Padhraig GormleyAarno Palotie
Jun 28, 2016·American Journal of Human Genetics·Huwenbo ShiBogdan Pasaniuc
Jan 18, 2017·Annals of Clinical and Translational Neurology·Sarah A GaglianoMichael E Weale
Feb 28, 2017·American Journal of Human Genetics·Nicholas MancusoBogdan Pasaniuc
Jun 18, 2017·Cell·Evan A BoyleJonathan Pritchard
Oct 24, 2017·Nature Genetics·Halit OngenEmmanouil T Dermitzakis

Citations

Apr 28, 2018·Nature Genetics·Naomi R WrayMajor Depressive Disorder Working Group of the Psychiatric Genomics Consortium
Nov 21, 2018·Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration
Dec 30, 2018·American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics·Christopher HübelGerome Breen
Jan 22, 2019·Nature Communications·Simon HaworthBeate St Pourcain
Mar 3, 2019·Bioinformatics·Guangsheng PeiPeilin Jia
Mar 13, 2019·Bioinformatics·Saori Sakaue, Yukinori Okada
May 19, 2018·Nature Communications·Momoko HorikoshiJohn R B Perry
Nov 5, 2019·Nucleic Acids Research·Peilin JiaZhongming Zhao
Mar 3, 2019·Nature Communications·Yang I LiTowfique Raj
Nov 22, 2019·Nature·Deborah J ThompsonJohn R B Perry
Dec 6, 2019·American Journal of Hematology·Xu ZhangVictor R Gordeuk
Jan 9, 2020·Nature Reviews. Genetics·Idan Hekselman, Esti Yeger-Lotem
Jan 23, 2020·Cells·Arkadiy K GolovAnd Vera E Golimbet
Sep 20, 2019·Science Advances·Abolfazl Doostparast TorshiziKai Wang
Jan 10, 2020·Nature·Melina ClaussnitzerMark I McCarthy
Nov 30, 2019·Immunological Reviews·Tiffany AmariutaSoumya Raychaudhuri
Feb 28, 2020·Human Reproduction·Sally MortlockGrant W Montgomery
Feb 28, 2020·Nature·Daniel B Graham, Ramnik J Xavier
Mar 24, 2020·Nature Genetics·Michael B FernandoKristen J Brennand
Oct 9, 2019·Human Molecular Genetics·Bryce van de GeijnAlkes L Price
Apr 20, 2020·International Journal of Epidemiology·Katherine M SiewertThe International Headache Genetics Consortium
May 15, 2020·Circulation·Nathan R TuckerPatrick T Ellinor
Sep 25, 2019·Nature Genetics·Nadine SchrodeKristen J Brennand
Jan 3, 2020·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Nina Roth MotaAlejandro Arias Vásquez
Jun 23, 2020·Human Molecular Genetics·Stefano BertoGenevieve Konopka
Sep 6, 2020·Brain : a Journal of Neurology·Niccolò E MencacciMina Ryten
May 3, 2019·Nature Genetics·Eli A StahlBipolar Disorder Working Group of the Psychiatric Genomics Consortium
Apr 22, 2019·Acta Neuropathologica·Javier Alegre-AbarrateguiChristos Proukakis
Jul 3, 2019·American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics·Lingfei LiuRanran Song
Jul 31, 2019·Nature Neuroscience·Joel GelernterDepartment of Veterans Affairs Cooperative Studies Program (#575B) and Million Veteran Program
Mar 21, 2020·Science·Katrina L GrasbyEnhancing NeuroImaging Genetics through Meta-Analysis Consortium (ENIGMA)—Genetics working group
Sep 20, 2020·Journal of Human Genetics·Masato Akiyama
Sep 23, 2020·Proceedings of the National Academy of Sciences of the United States of America·Kevin M AndersonAvram J Holmes
Jan 16, 2019·Nature Genetics·Bart M L BaselmansMeike Bartels
Feb 12, 2020·Nature Medicine·Katherine S RuthJohn R B Perry
Jul 31, 2020·Nature·Wouter MeulemanJohn Stamatoyannopoulos
May 13, 2020·Molecular Psychiatry·S Fleur W MeddensPhilipp D Koellinger
Oct 2, 2020·Communications Biology·Katerina TrajanoskaFernando Rivadeneira
Jul 5, 2018·Nature Communications·Felix R DayJohn R B Perry
Apr 25, 2018·Nature Reviews. Genetics·Ross Cloney
Dec 12, 2018·Nature Communications·International League Against Epilepsy Consortium on Complex Epilepsies
Jun 10, 2020·Nature Communications·Daniel Trejo BanosMatthew R Robinson
Jun 13, 2020·Nature Reviews. Neurology·Olav SmelandOle A Andreassen
May 23, 2018·Nature Genetics·Nathan G SkeneJens Hjerling-Leffler
Jan 13, 2019·The Journal of Headache and Pain·Arn M J M van den MaagdenbergVerneri Anttila
Mar 31, 2019·Nature Genetics·Michael WainbergAnshul Kundaje
Oct 12, 2019·Brain : a Journal of Neurology·Regina H ReynoldsSarah A Gagliano Taliun
Jul 21, 2019·Nature Communications·Kyoko WatanabeDanielle Posthuma
May 20, 2020·Nature Genetics·Douglas W YaoAlexander Gusev
May 15, 2020·Molecular Psychiatry·Amanda J PriceDaniel R Weinberger
Sep 22, 2020·ELife·Pascal N TimshelTune H Pers
Aug 9, 2020·Journal of the American Society of Nephrology : JASN·Yong LiMatthias Wuttke
Jun 27, 2019·Nature Communications·Dmitry ShunginIngegerd Johansson
Feb 26, 2019·Nature Genetics·Phuwanat SakornsakolpatInternational COPD Genetics Consortium
Oct 19, 2019·Nature Communications·Chikashi TeraoYoichiro Kamatani
Jun 20, 2020·BMC Bioinformatics·Vincent LavilleCHARGE Gene-Lifestyle Interactions Working Group
Oct 28, 2020·Movement Disorders : Official Journal of the Movement Disorder Society·Alexey ShadrinManu Sharma
Nov 20, 2020·Nucleic Acids Research·Yulin DaiZhongming Zhao
Dec 17, 2020·American Journal of Human Genetics·Andrew R MardersteinAndrew G Clark
Dec 29, 2020·Computational and Structural Biotechnology Journal·Juman JubranEsti Yeger-Lotem
Oct 29, 2020·Cell Reports·Margarida Cardoso-MoreiraHenrik Kaessmann
Dec 7, 2020·Biological Psychiatry·Lorenza Dall'AglioOliver Pain
Jul 22, 2020·The Journal of Allergy and Clinical Immunology·Zhaozhong ZhuLiming Liang
Feb 16, 2021·Frontiers in Genetics·Huanhuan ZhuXiang Zhou
Feb 10, 2021·European Journal of Human Genetics : EJHG·Matthew AguirreManuel A Rivas
Nov 20, 2020·The New England Journal of Medicine·Messoud Ashina
Nov 18, 2020·Nature Neuroscience·Kayla G TownsleyLaura M Huckins
Jan 9, 2021·Nature Genetics·Perline A DemangeMichel G Nivard
Jan 6, 2021·Trends in Molecular Medicine·Christopher W Fell, Vanja Nagy
Mar 2, 2021·The International Journal of Eating Disorders·Christopher HübelNadia Micali
Jan 28, 2021·Annals of Neurology·Maren Stolp AndersenInternational Parkinson's Disease Genomics Consortium
Mar 6, 2021·Nature Medicine·Meng Xiao HeEliezer M Van Allen
Apr 2, 2021·Nature Communications·Hyeonsoo JeongSoojin V Yi
Mar 29, 2021·Lancet·Messoud AshinaPeter J Goadsby
Apr 9, 2021·Proceedings of the National Academy of Sciences of the United States of America·Brooke SheppardAndy Dahl
Feb 25, 2021·Circulation. Genomic and Precision Medicine·Valentin Bon-BaretPatrick Mathieu
May 1, 2021·Biomedicines·Shi-Xun Ma, Su Bin Lim
Aug 21, 2020·Cold Spring Harbor Perspectives in Medicine·Eleonora PorcuZoltán Kutalik
Nov 28, 2020·The European Respiratory Journal·Satu StrauszFinnGen research group
May 14, 2021·Nature Human Behaviour·Abdel Abdellaoui, Karin J H Verweij
Mar 18, 2021·Cancer Research·Viola FanfaniGiovanni Stracquadanio
May 19, 2021·Nature Communications·Torbjørn ElvsåshagenTobias Kaufmann
May 22, 2021·PLoS Computational Biology·Arunabha MajumdarBogdan Pasaniuc
Mar 21, 2021·Neuro-oncology·Quinn T OstromMelissa L Bondy

Methods Mentioned

BETA
RNA-seq

Related Concepts

Related Feeds

Bipolar Disorder

Bipolar disorder is characterized by manic and/or depressive episodes and associated with uncommon shifts in mood, activity levels, and energy. Discover the latest research this illness here.