Single-Tissue and Cross-Tissue Heritability of Gene Expression Via Identity-by-Descent in Related or Unrelated Individuals
Family studies of individual tissues have shown that gene expression traits are genetically heritable. Here, we investigate cis and trans components of heritability both within and across tissues by applying variance-components methods to 722 Icelanders from family cohorts, using identity-by-descent (IBD) estimates from long-range phased genome-wide SNP data and gene expression measurements for ∼19,000 genes in blood and adipose tissue. We estimate the proportion of gene expression heritability attributable to cis regulation as 37% in blood and 24% in adipose tissue. Our results indicate that the correlation in gene expression measurements across these tissues is primarily due to heritability at cis loci, whereas there is little sharing of trans regulation across tissues. One implication of this finding is that heritability in tissues composed of heterogeneous cell types is expected to be more dominated by cis regulation than in tissues composed of more homogeneous cell types, consistent with our blood versus adipose results as well as results of previous studies in lymphoblastoid cell lines. Finally, we obtained similar estimates of the cis components of heritability using IBD between unrelated individuals, indicating that transgenerational epigenetic inheritance does not contribute substantially to the “missing heritability” of gene expression in these tissue types.
Vyšlo v časopise:
Single-Tissue and Cross-Tissue Heritability of Gene Expression Via Identity-by-Descent in Related or Unrelated Individuals. PLoS Genet 7(2): e32767. doi:10.1371/journal.pgen.1001317
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1001317
Souhrn
Family studies of individual tissues have shown that gene expression traits are genetically heritable. Here, we investigate cis and trans components of heritability both within and across tissues by applying variance-components methods to 722 Icelanders from family cohorts, using identity-by-descent (IBD) estimates from long-range phased genome-wide SNP data and gene expression measurements for ∼19,000 genes in blood and adipose tissue. We estimate the proportion of gene expression heritability attributable to cis regulation as 37% in blood and 24% in adipose tissue. Our results indicate that the correlation in gene expression measurements across these tissues is primarily due to heritability at cis loci, whereas there is little sharing of trans regulation across tissues. One implication of this finding is that heritability in tissues composed of heterogeneous cell types is expected to be more dominated by cis regulation than in tissues composed of more homogeneous cell types, consistent with our blood versus adipose results as well as results of previous studies in lymphoblastoid cell lines. Finally, we obtained similar estimates of the cis components of heritability using IBD between unrelated individuals, indicating that transgenerational epigenetic inheritance does not contribute substantially to the “missing heritability” of gene expression in these tissue types.
Zdroje
1. CooksonW
LiangL
AbecasisG
MoffattM
LathropM
2009 Mapping complex disease traits with global gene expression. Nat Rev Genet 10 184 194
2. SchadtEE
MonksSA
DrakeTA
LusisAJ
CheN
2003 Genetics of gene expression surveyed in maize, mouse and man. Nature 422 297 302
3. MorleyM
MolonyCM
WeberTM
DevlinJL
EwensKG
2004 Genetic analysis of genome-wide variation in human gene expression. Nature 430 743 747
4. GiladY
RifkinSA
PritchardJK
2008 Revealing the architecture of gene regulation: the promise of eQTL studies. Trends Genet 24 408 415
5. CheungVG
NayakRR
WangIX
ElwynS
CousinsSM
MorleyM
SpielmanRS
Polymorphic cis- and trans-regulation of human gene expression. PLoS Biol 8 e1000480 doi:10.1371/journal.pbio.1000480
6. CheslerEJ
LuL
ShouS
QuY
GuJ
2005 Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function. Nat Genet 37 233 242
7. WilliamsRB
CotsapasCJ
CowleyMJ
ChanE
NottDJ
2006 Normalization procedures and detection of linkage signal in genetical-genomics experiments. Nat Genet 38 855 856; author reply 856-859
8. PetrettoE
MangionJ
DickensNJ
CookSA
KumaranMK
2006 Heritability and tissue specificity of expression quantitative trait loci. PLoS Genet 2 e172 doi:10.1371/journal.pgen.0020172
9. PetrettoE
BottoloL
LangleySR
HeinigM
McDermott-RoeC
2010 New insights into the genetic control of gene expression using a Bayesian multi-tissue approach. PLoS Comput Biol 6 e1000737 doi:10.1371/journal.pcbi.1000737
10. MonksSA
LeonardsonA
ZhuH
CundiffP
PietrusiakP
2004 Genetic inheritance of gene expression in human cell lines. Am J Hum Genet 75 1094 1105
11. EmilssonV
ThorleifssonG
ZhangB
LeonardsonAS
ZinkF
2008 Genetics of gene expression and its effect on disease. Nature 452 423 428
12. StrangerBE
NicaAC
ForrestMS
DimasA
BirdCP
2007 Population genomics of human gene expression. Nat Genet 39 1217 1224
13. DixonAL
LiangL
MoffattMF
ChenW
HeathS
2007 A genome-wide association study of global gene expression. Nat Genet 39 1202 1207
14. VisscherPM
HillWG
WrayNR
2008 Heritability in the genomics era--concepts and misconceptions. Nat Rev Genet 9 255 266
15. KongA
MassonG
FriggeML
GylfasonA
ZusmanovichP
2008 Detection of sharing by descent, long-range phasing and haplotype imputation. Nat Genet 40 1068 1075
16. PriceAL
PattersonN
HancksDC
MyersS
ReichD
2008 Effects of cis and trans genetic ancestry on gene expression in African Americans. PLoS Genet 4 e1000294 doi:10.1371/journal.pgen.1000294
17. McCarthyMI
HirschhornJN
2008 Genome-wide association studies: potential next steps on a genetic journey. Hum Mol Genet 17 R156 165
18. MaherB
2008 Personal genomes: The case of the missing heritability. Nature 456 18 21
19. ManolioTA
CollinsFS
CoxNJ
GoldsteinDB
HindorffLA
2009 Finding the missing heritability of complex diseases. Nature 461 747 753
20. EichlerEE
FlintJ
GibsonG
KongA
LealSM
2010 Missing heritability and strategies for finding the underlying causes of complex disease. Nat Rev Genet 11 446 450
21. KaminskyZA
TangT
WangSC
PtakC
OhGH
2009 DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 41 240 245
22. YoungsonNA
WhitelawE
2008 Transgenerational epigenetic effects. Annu Rev Genomics Hum Genet 9 233 257
23. JablonkaE
RazG
2009 Transgenerational epigenetic inheritance: prevalence, mechanisms, and implications for the study of heredity and evolution. Q Rev Biol 84 131 176
24. AmosCI
1994 Robust variance-components approach for assessing genetic linkage in pedigrees. Am J Hum Genet 54 535 543
25. MacgregorS
CornesBK
MartinNG
VisscherPM
2006 Bias, precision and heritability of self-reported and clinically measured height in Australian twins. Hum Genet 120 571 580
26. McRaeAF
MatigianNA
VadlamudiL
MulleyJC
MowryB
2007 Replicated effects of sex and genotype on gene expression in human lymphoblastoid cell lines. Hum Mol Genet 16 364 373
27. StrangerBE
MontgomerySB
DimasA
PartsL
IngleCE
Patterns of cis regulatory variation in diverse human populations. Submitted
28. The International HapMap 3 Consortium 2010 An integrated haplotype map of rare and common genetic variation in diverse human populations. Nature 467 52 8
29. HelgasonA
PalssonS
GudbjartssonDF
KristjanssonT
StefanssonK
2008 An association between the kinship and fertility of human couples. Science 319 813 816
30. The International HapMap Consortium 2007 A second generation human haplotype map of over 3.1 million SNPs. Nature 449 851 61
31. GusevA
LoweJK
StoffelM
DalyMJ
AltshulerD
2009 Whole population, genome-wide mapping of hidden relatedness. Genome Res 19 318 326
32. AstoriG
VignatiF
BardelliS
TubioM
GolaM
2007 "In vitro" and multicolor phenotypic characterization of cell subpopulations identified in fresh human adipose tissue stromal vascular fraction and in the derived mesenchymal stem cells. J Transl Med 5 55
33. JosephsonB
DahlbergG
1952 Variations in the cell-content and chemical composition of the human blood due to age, sex and season. Scand J Clin Lab Invest 4 216 236
34. CheungVG
SpielmanRS
2009 Genetics of human gene expression: mapping DNA variants that influence gene expression. Nat Rev Genet 10 595 604
35. SchadtEE
MolonyC
ChudinE
HaoK
YangX
2008 Mapping the genetic architecture of gene expression in human liver. PLoS Biol 6 e107 doi:10.1371/journal.pbio.0060107
36. DimasAS
DeutschS
StrangerBE
MontgomerySB
BorelC
2009 Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325 1246 1250
37. IdaghdourY
CzikaW
ShiannaKV
LeeSH
VisscherPM
2010 Geographical genomics of human leukocyte gene expression variation in southern Morocco. Nat Genet 42 62 67
38. ChoyE
YelenskyR
BonakdarS
PlengeRM
SaxenaR
2008 Genetic analysis of human traits in vitro: drug response and gene expression in lymphoblastoid cell lines. PLoS Genet 4 e1000287 doi:10.1371/journal.pgen.1000287
39. Shen-OrrSS
TibshiraniR
KhatriP
BodianDL
StaedtlerF
2010 Cell type-specific gene expression differences in complex tissues. Nat Methods 7 287 289
40. MorganHD
SutherlandHG
MartinDI
WhitelawE
1999 Epigenetic inheritance at the agouti locus in the mouse. Nat Genet 23 314 318
41. RakyanVK
ChongS
ChampME
CuthbertPC
MorganHD
2003 Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc Natl Acad Sci U S A 100 2538 2543
42. KennyEE
GusevA
RiegelK
LutjohannD
LoweJK
2009 Systematic haplotype analysis resolves a complex plasma plant sterol locus on the Micronesian Island of Kosrae. Proc Natl Acad Sci U S A 106 13886 13891
43. KangHM
SulJH
ServiceSK
ZaitlenNA
KongSY
2010 Variance component model to account for sample structure in genome-wide association studies. Nat Genet 42 348 354
44. YangJ
BenyaminB
McEvoyBP
GordonS
HendersAK
2010 Common SNPs explain a large proportion of the heritability for human height. Nat Genet 42 565 569
45. PowellJE
VisscherPM
GoddardME
2010 Reconciling the analysis of IBD and IBS in complex trait studies. Nat Rev Genet
46. VisscherPM
MedlandSE
FerreiraMA
MorleyKI
ZhuG
2006 Assumption-free estimation of heritability from genome-wide identity-by-descent sharing between full siblings. PLoS Genet 2 e41 doi:10.1371/journal.pgen.0020041
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Genetika Reprodukčná medicínaČlánok vyšiel v časopise
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