title: Tissue-specific effects of genetic and epigenetic variation on gene regulation and splicing.
abstract: Understanding how genetic variation affects distinct cellular phenotypes, such as gene expression levels, alternative splicing and DNA methylation levels, is essential for better understanding of complex diseases and traits. Furthermore, how inter-individual variation of DNA methylation is associated to gene expression is just starting to be studied. In this study, we use the GenCord cohort of 204 newborn Europeans' lymphoblastoid cell lines, T-cells and fibroblasts derived from umbilical cords. The samples were previously genotyped for 2.5 million SNPs, mRNA-sequenced, and assayed for methylation levels in 482,421 CpG sites. We observe that methylation sites associated to expression levels are enriched in enhancers, gene bodies and CpG island shores. We show that while the correlation between DNA methylation and gene expression can be positive or negative, it is very consistent across cell-types. However, this epigenetic association to gene expression appears more tissue-specific than the genetic effects on gene expression or DNA methylation (observed in both sharing estimations based on P-values and effect size correlations between cell-types). This predominance of genetic effects can also be reflected by the observation that allele specific expression differences between individuals dominate over tissue-specific effects. Additionally, we discover genetic effects on alternative splicing and interestingly, a large amount of DNA methylation correlating to alternative splicing, both in a tissue-specific manner. The locations of the SNPs and methylation sites involved in these associations highlight the participation of promoter proximal and distant regulatory regions on alternative splicing. Overall, our results provide high-resolution analyses showing how genome sequence variation has a broad effect on cellular phenotypes across cell-types, whereas epigenetic factors provide a secondary layer of variation that is more tissue-specific. Furthermore, the details of how this tissue-specificity may vary across inter-relations of molecular traits, and where these are occurring, can yield further insights into gene regulation and cellular biology as a whole.
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland; Swiss Institute of Bioinformatics (SIB), Geneva, Switzerland.
authors: Maria
authors: M
authors: Gutierrez-Arcelus
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland; Swiss Institute of Bioinformatics (SIB), Geneva, Switzerland.
authors: Halit
authors: H
authors: Ongen
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland; Swiss Institute of Bioinformatics (SIB), Geneva, Switzerland.
authors: Tuuli
authors: T
authors: Lappalainen
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Departments of Pathology and Genetics, Stanford University, Stanford, California, United States of America.
authors: Stephen B
authors: SB
authors: Montgomery
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland; Swiss Institute of Bioinformatics (SIB), Geneva, Switzerland.
authors: Alfonso
authors: A
authors: Buil
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland; Swiss Institute of Bioinformatics (SIB), Geneva, Switzerland.
authors: Alisa
authors: A
authors: Yurovsky
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland; Swiss Institute of Bioinformatics (SIB), Geneva, Switzerland.
authors: Julien
authors: J
authors: Bryois
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland; Swiss Institute of Bioinformatics (SIB), Geneva, Switzerland.
authors: Ismael
authors: I
authors: Padioleau
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland; Swiss Institute of Bioinformatics (SIB), Geneva, Switzerland.
authors: Luciana
authors: L
authors: Romano
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland; Swiss Institute of Bioinformatics (SIB), Geneva, Switzerland.
authors: Alexandra
authors: A
authors: Planchon
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland.
authors: Emilie
authors: E
authors: Falconnet
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland.
authors: Deborah
authors: D
authors: Bielser
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland.
authors: Maryline
authors: M
authors: Gagnebin
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors: Thomas
authors: T
authors: Giger
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
authors: Christelle
authors: C
authors: Borel
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland.
authors: Audrey
authors: A
authors: Letourneau
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland.
authors: Periklis
authors: P
authors: Makrythanasis
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland.
authors: Michel
authors: M
authors: Guipponi
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland.
authors: Corinne
authors: C
authors: Gehrig
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland.
authors: Stylianos E
authors: SE
authors: Antonarakis
authors: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland; Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland; Swiss Institute of Bioinformatics (SIB), Geneva, Switzerland; Center of Excellence in Genomic Medicine Research, KingAbdulaziz University, Jeddah, Saudi Arabia.
authors: Emmanouil T
authors: ET
authors: Dermitzakis
mesh_terms: D000483:Alleles; D017398:Alternative Splicing / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D007231:Infant, Newborn; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics
references: Nature. 2013 Sep 26;501(7468):506-11
references: 24037378
references: Genome Biol. 2013;14(8):R83
references: 23958281
references: Nat Genet. 2008 Feb;40(2):225-31
references: 18193047
references: Cell. 2008 Jan 25;132(2):311-22
references: 18243105
references: Am J Hum Genet. 2009 Feb;84(2):210-23
references: 19200528
references: Nat Rev Genet. 2009 Mar;10(3):184-94
references: 19223927
references: PLoS Biol. 2008 Dec 23;6(12):e1
references: 19222302
references: Hum Mol Genet. 2009 Apr 15;18(R1):R1-8
references: 19297395
references: Science. 2009 May 15;324(5929):930-5
references: 19372391
references: Science. 2009 May 15;324(5929):929-30
references: 19372393
references: Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9362-7
references: 19474294
references: Bioinformatics. 2009 Jul 15;25(14):1754-60
references: 19451168
references: PLoS Genet. 2009 Aug;5(8):e1000608
references: 19680542
references: Science. 2009 Sep 4;325(5945):1246-50
references: 19644074
references: Nature. 2009 Nov 19;462(7271):315-22
references: 19829295
references: PLoS Genet. 2009 Dec;5(12):e1000766
references: 20011102
references: Nucleic Acids Res. 2010 Jan;38(Database issue):D620-5
references: 19920125
references: Genome Res. 2010 Mar;20(3):320-31
references: 20133333
references: Bioinformatics. 2010 Mar 15;26(6):841-2
references: 20110278
references: Am J Hum Genet. 2010 Mar 12;86(3):411-9
references: 20215007
references: Nature. 2010 Apr 1;464(7289):773-7
references: 20220756
references: Nature. 2010 Apr 1;464(7289):768-72
references: 20220758
references: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5
references: 12883005
references: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D493-6
references: 14681465
references: Nat Rev Genet. 2004 May;5(5):389-96
references: 15168696
references: Science. 1975 Jan 24;187(4173):226-32
references: 1111098
references: Cytogenet Cell Genet. 1975;14(1):9-25
references: 1093816
references: Science. 1991 Jan 11;251(4990):186-9
references: 1987636
references: Nat Rev Genet. 2005 Aug;6(8):597-610
references: 16136652
references: Nature. 2005 Oct 27;437(7063):1365-9
references: 16251966
references: Genome Res. 2006 Mar;16(3):383-93
references: 16449502
references: PLoS Genet. 2005 Dec;1(6):e78
references: 16362079
references: Genome Biol. 2006;7 Suppl 1:S4.1-9
references: 16925838
references: Science. 2007 Feb 23;315(5815):1141-3
references: 17322062
references: Nature. 2007 Jun 14;447(7146):799-816
references: 17571346
references: Nat Genet. 2007 Oct;39(10):1217-24
references: 17873874
references: PLoS Genet. 2010 Apr;6(4):e1000895
references: 20369022
references: PLoS Genet. 2010 May;6(5):e1000952
references: 20485568
references: Nature. 2010 Jul 8;466(7303):253-7
references: 20613842
references: Bioinformatics. 2010 Aug 15;26(16):2069-70
references: 20562413
references: Nat Biotechnol. 2010 Aug;28(8):817-25
references: 20657582
references: PLoS Genet. 2011;7(2):e1002003
references: 21304890
references: Genome Res. 2011 Apr;21(4):545-54
references: 21173033
references: Nature. 2011 May 5;473(7345):43-9
references: 21441907
references: Nat Rev Genet. 2011 Aug;12(8):529-41
references: 21747404
references: PLoS Genet. 2011 Aug;7(8):e1002228
references: 21852959
references: Am J Hum Genet. 2011 Sep 9;89(3):459-63
references: 21907014
references: Genome Biol. 2011;12(1):R10
references: 21251332
references: Nature. 2011 Nov 3;479(7371):74-9
references: 21964334
references: Nature. 2011 Dec 22;480(7378):490-5
references: 22170606
references: PLoS Genet. 2012 Jan;8(1):e1002431
references: 22275870
references: Nat Rev Genet. 2012 Jul;13(7):484-92
references: 22641018
references: Nature. 2012 Sep 6;489(7414):57-74
references: 22955616
references: Nature. 2012 Sep 6;489(7414):75-82
references: 22955617
references: Nat Genet. 2012 Oct;44(10):1084-9
references: 22941192
references: Nat Genet. 2012 Nov;44(11):1236-42
references: 23064414
references: Nature. 2012 Nov 1;491(7422):56-65
references: 23128226
references: PLoS Genet. 2012;8(10):e1002998
references: 23133393
references: Nucleic Acids Res. 2013 Jan;41(Database issue):D48-55
references: 23203987
references: Elife. 2013;2:e00523
references: 23755361
references: Nat Genet. 2013 Aug;45(8):852-9
references: 23793028
references: Nature. 2013 Aug 22;500(7463):477-81
references: 23925113
references: Nature. 2008 Mar 27;452(7186):423-8
references: 18344981
references: Nat Genet. 2008 May;40(5):492-3
references: 18443581
references: PLoS Genet. 2008 Oct;4(10):e1000214
references: 18846210
references: Hum Genet. 2009 Feb;125(1):81-93
references: 19052777