The architecture of gene regulatory variation across multiple human tissues: the MuTHER study.
While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, an...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Public Library of Science
2011
|
| _version_ | 1826282030155956224 |
|---|---|
| author | Nica, A Parts, L Glass, D Nisbet, J Barrett, A Sekowska, M Travers, M Potter, S Grundberg, E Small, K Hedman, A Bataille, V Tzenova Bell, J Surdulescu, G Dimas, A Ingle, C Nestle, F di Meglio, P Min, J Wilk, A Hammond, C Hassanali, N Yang, T Montgomery, S O'Rahilly, S Lindgren, C Zondervan, K Soranzo, N Barroso, I Durbin, R Ahmadi, K Deloukas, P McCarthy, M Dermitzakis, E Spector, T |
| author_facet | Nica, A Parts, L Glass, D Nisbet, J Barrett, A Sekowska, M Travers, M Potter, S Grundberg, E Small, K Hedman, A Bataille, V Tzenova Bell, J Surdulescu, G Dimas, A Ingle, C Nestle, F di Meglio, P Min, J Wilk, A Hammond, C Hassanali, N Yang, T Montgomery, S O'Rahilly, S Lindgren, C Zondervan, K Soranzo, N Barroso, I Durbin, R Ahmadi, K Deloukas, P McCarthy, M Dermitzakis, E Spector, T |
| author_sort | Nica, A |
| collection | OXFORD |
| description | While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis--MCTA) permits immediate replication of eQTLs using co-twins (93%-98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits. |
| first_indexed | 2024-03-07T00:37:43Z |
| format | Journal article |
| id | oxford-uuid:81fe0051-7cff-43b8-a0de-e3dcdf2e39fc |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:37:43Z |
| publishDate | 2011 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:81fe0051-7cff-43b8-a0de-e3dcdf2e39fc2022-03-26T21:34:12ZThe architecture of gene regulatory variation across multiple human tissues: the MuTHER study.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:81fe0051-7cff-43b8-a0de-e3dcdf2e39fcEnglishSymplectic Elements at OxfordPublic Library of Science2011Nica, AParts, LGlass, DNisbet, JBarrett, ASekowska, MTravers, MPotter, SGrundberg, ESmall, KHedman, ABataille, VTzenova Bell, JSurdulescu, GDimas, AIngle, CNestle, Fdi Meglio, PMin, JWilk, AHammond, CHassanali, NYang, TMontgomery, SO'Rahilly, SLindgren, CZondervan, KSoranzo, NBarroso, IDurbin, RAhmadi, KDeloukas, PMcCarthy, MDermitzakis, ESpector, TWhile there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis--MCTA) permits immediate replication of eQTLs using co-twins (93%-98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits. |
| spellingShingle | Nica, A Parts, L Glass, D Nisbet, J Barrett, A Sekowska, M Travers, M Potter, S Grundberg, E Small, K Hedman, A Bataille, V Tzenova Bell, J Surdulescu, G Dimas, A Ingle, C Nestle, F di Meglio, P Min, J Wilk, A Hammond, C Hassanali, N Yang, T Montgomery, S O'Rahilly, S Lindgren, C Zondervan, K Soranzo, N Barroso, I Durbin, R Ahmadi, K Deloukas, P McCarthy, M Dermitzakis, E Spector, T The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. |
| title | The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. |
| title_full | The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. |
| title_fullStr | The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. |
| title_full_unstemmed | The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. |
| title_short | The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. |
| title_sort | architecture of gene regulatory variation across multiple human tissues the muther study |
| work_keys_str_mv | AT nicaa thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT partsl thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT glassd thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT nisbetj thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT barretta thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT sekowskam thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT traversm thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT potters thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT grundberge thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT smallk thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT hedmana thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT bataillev thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT tzenovabellj thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT surdulescug thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT dimasa thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT inglec thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT nestlef thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT dimegliop thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT minj thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT wilka thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT hammondc thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT hassanalin thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT yangt thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT montgomerys thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT orahillys thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT lindgrenc thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT zondervank thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT soranzon thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT barrosoi thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT durbinr thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT ahmadik thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT deloukasp thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT mccarthym thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT dermitzakise thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT spectort thearchitectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT nicaa architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT partsl architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT glassd architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT nisbetj architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT barretta architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT sekowskam architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT traversm architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT potters architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT grundberge architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT smallk architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT hedmana architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT bataillev architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT tzenovabellj architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT surdulescug architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT dimasa architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT inglec architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT nestlef architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT dimegliop architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT minj architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT wilka architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT hammondc architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT hassanalin architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT yangt architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT montgomerys architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT orahillys architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT lindgrenc architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT zondervank architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT soranzon architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT barrosoi architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT durbinr architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT ahmadik architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT deloukasp architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT mccarthym architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT dermitzakise architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy AT spectort architectureofgeneregulatoryvariationacrossmultiplehumantissuesthemutherstudy |