The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
received:
01
12
2021
accepted:
27
01
2023
entrez:
14
3
2023
pubmed:
15
3
2023
medline:
16
3
2023
Statut:
ppublish
Résumé
Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.
Identifiants
pubmed: 36914876
doi: 10.1038/s41588-023-01323-z
pii: 10.1038/s41588-023-01323-z
pmc: PMC10042257
mid: NIHMS1873427
doi:
Types de publication
Meta-Analysis
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
423-436Subventions
Organisme : Medical Research Council
ID : MR/K011480/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 084766
Pays : United Kingdom
Organisme : NICHD NIH HHS
ID : R01 HD089511
Pays : United States
Organisme : Wellcome Trust (Wellcome)
ID : WT084766/Z/08/Z
Investigateurs
Kari Stefansson
(K)
Mette Nyegaard
(M)
Paivi Harkki
(P)
Oskari Heikinheimo
(O)
Johannes Kettunen
(J)
Venla Kurra
(V)
Hannele Laivuori
(H)
Outi Uimari
(O)
Geneviève Galarneau
(G)
Caterina Clementi
(C)
Piraye Yurttas-Beim
(P)
Pierre Fontanillas
(P)
Joyce Y Tung
(JY)
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
Références
Zondervan, K. T., Becker, C. M. & Missmer, S. A. Endometriosis. N. Engl. J. Med. 382, 1244–1256 (2020).
pubmed: 32212520
doi: 10.1056/NEJMra1810764
Nnoaham, K. E. et al. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil. Steril. 96, 366–373 (2011).
pubmed: 21718982
pmcid: 3679489
doi: 10.1016/j.fertnstert.2011.05.090
Revised, A. S. R. M. American society for reproductive medicine classification of endometriosis: 1996. Fertil. Steril. 67, 817–821 (1997).
doi: 10.1016/S0015-0282(97)81391-X
Saha, R. et al. Heritability of endometriosis. Fertil. Steril. 104, 947–952 (2015).
pubmed: 26209831
doi: 10.1016/j.fertnstert.2015.06.035
Treloar, S. A., O’Connor, D. T., O’Connor, V. M. & Martin, N. G. Genetic influences on endometriosis in an Australian twin sample. sueT@qimr.edu.au. Fertil. Steril. 71, 701–710 (1999).
pubmed: 10202882
doi: 10.1016/S0015-0282(98)00540-8
Lee, S. H. et al. Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer’s disease, multiple sclerosis and endometriosis. Hum. Mol. Genet. 22, 832–841 (2013).
pubmed: 23193196
doi: 10.1093/hmg/dds491
Zondervan, K. T. et al. Endometriosis. Nat. Rev. Dis. Primers 4, 9 (2018).
pubmed: 30026507
doi: 10.1038/s41572-018-0008-5
Sapkota, Y. et al. Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nat. Commun. 8, 15539 (2017).
pubmed: 28537267
pmcid: 5458088
doi: 10.1038/ncomms15539
Painter, J. N. et al. Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis. Nat. Genet. 43, 51–54 (2011).
pubmed: 21151130
doi: 10.1038/ng.731
Fung, J. N. et al. Genetic regulation of disease risk and endometrial gene expression highlights potential target genes for endometriosis and polycystic ovarian syndrome. Sci. Rep. 8, 11424 (2018).
pubmed: 30061686
pmcid: 6065421
doi: 10.1038/s41598-018-29462-y
Mortlock, S. et al. Tissue specific regulation of transcription in endometrium and association with disease. Hum. Reprod. 35, 377–393 (2020).
pubmed: 32103259
pmcid: 7048713
doi: 10.1093/humrep/dez279
Võsa, U. et al. Unraveling the polygenic architecture of complex traits using blood eQTL meta-analysis. Nat. Genet. 53, 1300–1310 (2021).
pubmed: 34475573
pmcid: 8432599
doi: 10.1038/s41588-021-00913-z
McRae, A. F. et al. Identification of 55,000 replicated DNA methylation QTL. Sci. Rep. 8, 17605 (2018).
pubmed: 30514905
pmcid: 6279736
doi: 10.1038/s41598-018-35871-w
Mortlock, S. et al. Genetic regulation of methylation in human endometrium and blood and gene targets for reproductive diseases. Clin. Epigenetics 11, 49 (2019).
pubmed: 30871624
pmcid: 6416889
doi: 10.1186/s13148-019-0648-7
Zhu, Z. et al. Integration of summary data from GWAS and eQTL studies predicts complex trait gene targets. Nat. Genet. 48, 481–487 (2016).
pubmed: 27019110
doi: 10.1038/ng.3538
Fung, J. N. et al. Functional evaluation of genetic variants associated with endometriosis near GREB1. Hum. Reprod. 30, 1263–1275 (2015).
pubmed: 25788566
doi: 10.1093/humrep/dev051
Jones, A. V. et al. Genome-wide association analysis of pain severity in dysmenorrhea identifies association at chromosome 1p13.2, near the nerve growth factor locus. Pain 157, 2571–2581 (2016).
pubmed: 27454463
pmcid: 5436737
doi: 10.1097/j.pain.0000000000000678
Barneo-Munoz, M. et al. Lack of GDAP1 induces neuronal calcium and mitochondrial defects in a knockout mouse model of charcot-marie-tooth neuropathy. PLoS Genet. 11, e1005115 (2015).
pubmed: 25860513
pmcid: 4393229
doi: 10.1371/journal.pgen.1005115
Ruth, K. S. et al. Using human genetics to understand the disease impacts of testosterone in men and women. Nat. Med. 26, 252–258 (2020).
pubmed: 32042192
pmcid: 7025895
doi: 10.1038/s41591-020-0751-5
Zhai, G. et al. Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms. PLoS Genet. 7, e1002025 (2011).
pubmed: 21533175
pmcid: 3077384
doi: 10.1371/journal.pgen.1002025
Rahmani, A., Shoae-Hassani, A., Keyhanvar, P., Kheradmand, D. & Darbandi-Azar, A. Dehydroepiandrosterone stimulates nerve growth factor and brain derived neurotrophic factor in cortical neurons. Adv. Pharm. Sci. 2013, 506191 (2013).
Maninger, N., Wolkowitz, O. M., Reus, V. I., Epel, E. S. & Mellon, S. H. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front. Neuroendocrinol. 30, 65–91 (2009).
pubmed: 19063914
doi: 10.1016/j.yfrne.2008.11.002
Obata, K. & Noguchi, K. BDNF in sensory neurons and chronic pain. Neurosci. Res. 55, 1–10 (2006).
pubmed: 16516994
doi: 10.1016/j.neures.2006.01.005
Browne, A. S. et al. Proteomic identification of neurotrophins in the eutopic endometrium of women with endometriosis. Fertil. Steril. 98, 713–719 (2012).
pubmed: 22717347
pmcid: 3432681
doi: 10.1016/j.fertnstert.2012.05.027
Wang, S. et al. BDNF and TrKB expression levels in patients with endometriosis and their associations with dysmenorrhoea. J. Ovarian Res. 15, 35 (2022).
pubmed: 35300713
pmcid: 8932107
doi: 10.1186/s13048-022-00963-9
Peng, B., Alotaibi, F. T., Sediqi, S., Bedaiwy, M. A. & Yong, P. J. Role of interleukin-1beta in nerve growth factor expression, neurogenesis and deep dyspareunia in endometriosis. Hum. Reprod. 35, 901–912 (2020).
pubmed: 32240297
pmcid: 7192531
doi: 10.1093/humrep/deaa017
Vitonis, A. F. et al. World endometriosis research foundation endometriosis phenome and biobanking harmonization project: II. Clinical and covariate phenotype data collection in endometriosis research. Fertil. Steril. 102, 1223–1232 (2014).
pubmed: 25256930
pmcid: 4252538
doi: 10.1016/j.fertnstert.2014.07.1244
Nathan, A. et al. The Wilms tumor protein Wt1 contributes to female fertility by regulating oviductal proteostasis. Hum. Mol. Genet. 26, 1694–1705 (2017).
pubmed: 28334862
pmcid: 5411738
doi: 10.1093/hmg/ddx075
O’Mara, T. A. et al. Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer. Endocr. Relat. Cancer 22, 851–861 (2015).
pubmed: 26330482
pmcid: 4559752
doi: 10.1530/ERC-15-0319
Marla, S. et al. Genetic risk factors for endometriosis near estrogen receptor 1 and coexpression of genes in this region in endometrium. Mol. Hum. Reprod. 27, gaaa082 (2021).
pubmed: 33394050
pmcid: 8453628
doi: 10.1093/molehr/gaaa082
Smith, S. B. et al. Epistasis between polymorphisms in COMT, ESR1, and GCH1 influences COMT enzyme activity and pain. Pain 155, 2390–2399 (2014).
pubmed: 25218601
pmcid: 4253645
doi: 10.1016/j.pain.2014.09.009
Martin, V. T. Ovarian hormones and pain response: a review of clinical and basic science studies. Gend. Med. 6, 168–192 (2009).
pubmed: 19406368
doi: 10.1016/j.genm.2009.03.006
Smith, Y. R. et al. Pronociceptive and antinociceptive effects of estradiol through endogenous opioid neurotransmission in women. J. Neurosci. 26, 5777–5785 (2006).
pubmed: 16723535
pmcid: 1808228
doi: 10.1523/JNEUROSCI.5223-05.2006
Bulik-Sullivan, B. et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 47, 1236–1241 (2015).
pubmed: 26414676
pmcid: 4797329
doi: 10.1038/ng.3406
Bulik-Sullivan, B. K. et al. LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015).
pubmed: 25642630
pmcid: 4495769
doi: 10.1038/ng.3211
Shafrir, A. L. et al. Risk for and consequences of endometriosis: a critical epidemiologic review. Best Pract. Res. Clin. Obstet. Gynaecol. 51, 1–15 (2018).
pubmed: 30017581
doi: 10.1016/j.bpobgyn.2018.06.001
Missmer, S. A. et al. Reproductive history and endometriosis among premenopausal women. Obstet. Gynecol. 104, 965–974 (2004).
pubmed: 15516386
doi: 10.1097/01.AOG.0000142714.54857.f8
Sampson, J. A. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am. J. Pathol. 3, 93–110 (1927).
pubmed: 19969738
pmcid: 1931779
Barban, N. et al. Genome-wide analysis identifies 12 loci influencing human reproductive behavior. Nat. Genet. 48, 1462–1472 (2016).
pubmed: 27798627
pmcid: 5695684
doi: 10.1038/ng.3698
As-Sanie, S. et al. Changes in regional gray matter volume in women with chronic pelvic pain: a voxel-based morphometry study. Pain 153, 1006–1014 (2012).
pubmed: 22387096
pmcid: 3613137
doi: 10.1016/j.pain.2012.01.032
Coxon, L., Horne, A. W. & Vincent, K. Pathophysiology of endometriosis-associated pain: a review of pelvic and central nervous system mechanisms. Best Pract. Res. Clin. Obstet. Gynaecol. 51, 53–67 (2018).
pubmed: 29525437
doi: 10.1016/j.bpobgyn.2018.01.014
Bajaj, P., Bajaj, P., Madsen, H. & Arendt-Nielsen, L. Endometriosis is associated with central sensitization: a psychophysical controlled study. J. Pain 4, 372–380 (2003).
pubmed: 14622679
doi: 10.1016/S1526-5900(03)00720-X
Berkley, K. J., Rapkin, A. J. & Papka, R. E. The pains of endometriosis. Science 308, 1587–1589 (2005).
pubmed: 15947176
doi: 10.1126/science.1111445
Vincent, K. et al. Dysmenorrhoea is associated with central changes in otherwise healthy women. Pain 152, 1966–1975 (2011).
pubmed: 21524851
doi: 10.1016/j.pain.2011.03.029
Elliott, L. T. et al. Genome-wide association studies of brain imaging phenotypes in UK Biobank. Nature 562, 210–216 (2018).
pubmed: 30305740
pmcid: 6786974
doi: 10.1038/s41586-018-0571-7
Kamat, M. A. et al. PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinformatics 35, 4851–4853 (2019).
pubmed: 31233103
pmcid: 6853652
doi: 10.1093/bioinformatics/btz469
Turley, P. et al. Multi-trait analysis of genome-wide association summary statistics using MTAG. Nat. Genet. 50, 229–237 (2018).
pubmed: 29292387
pmcid: 5805593
doi: 10.1038/s41588-017-0009-4
Ilad, R. S., Fleming, S. D., Bebington, C. R. & Murphy, C. R. Ubiquitin is associated with the survival of ectopic stromal cells in endometriosis. Reprod. Biol. Endocrinol. 2, 69 (2004).
pubmed: 15447789
pmcid: 534788
doi: 10.1186/1477-7827-2-69
Cheng, J., Deng, Y. & Zhou, J. Role of the ubiquitin system in chronic pain. Front. Mol. Neurosci. 14, 674914 (2021).
pubmed: 34122010
pmcid: 8194701
doi: 10.3389/fnmol.2021.674914
Garcia-Gomez, E. et al. Regulation of inflammation pathways and inflammasome by sex steroid hormones in endometriosis. Front. Endocrinol. 10, 935 (2019).
doi: 10.3389/fendo.2019.00935
Ding, Y. Q., Luo, H. & Qi, J. G. MHCII-restricted T helper cells: an emerging trigger for chronic tactile allodynia after nerve injuries. J. Neuroinflammation 17, 3 (2020).
pubmed: 31900220
pmcid: 6942353
doi: 10.1186/s12974-019-1684-0
Gougeon, A. Human ovarian follicular development: from activation of resting follicles to preovulatory maturation. Ann. Endocrinol. 71, 132–143 (2010).
doi: 10.1016/j.ando.2010.02.021
Jones, M. R. & Goodarzi, M. O. Genetic determinants of polycystic ovary syndrome: progress and future directions. Fertil. Steril. 106, 25–32 (2016).
pubmed: 27179787
doi: 10.1016/j.fertnstert.2016.04.040
Ruth, K. S. et al. Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause and impact female reproductive health. Hum. Reprod. 31, 473–481 (2016).
pubmed: 26732621
pmcid: 4716809
doi: 10.1093/humrep/dev318
Ruth, K. S. et al. Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes. Eur. J. Hum. Genet. 24, 284–290 (2016).
pubmed: 26014426
doi: 10.1038/ejhg.2015.102
Gregus, A. M., Levine, I. S., Eddinger, K. A., Yaksh, T. L. & Buczynski, M. W. Sex differences in neuroimmune and glial mechanisms of pain. Pain 162, 2186–2200 (2021).
pubmed: 34256379
pmcid: 8277970
Lenert, M. E., Avona, A., Garner, K. M., Barron, L. R. & Burton, M. D. Sensory neurons, neuroimmunity, and pain modulation by sex hormones. Endocrinology 162, bqab109 (2021).
pubmed: 34049389
pmcid: 8237991
doi: 10.1210/endocr/bqab109
Choi, E. J. et al. Comorbidity of gynecological and non-gynecological diseases with adenomyosis and endometriosis. Obstet. Gynecol. Sci. 60, 579–586 (2017).
pubmed: 29184867
pmcid: 5694733
doi: 10.5468/ogs.2017.60.6.579
Loughlin, A. M. et al. Method used to identify adenomyosis and potentially undiagnosed adenomyosis in a large, U.S. electronic health record database. Pharmacoepidemiol. Drug Saf. 30, 1675–1686 (2021).
pubmed: 34292640
doi: 10.1002/pds.5333
Powell, J. E. et al. Endometriosis risk alleles at 1p36.12 act through inverse regulation of CDC42 and LINC00339. Hum. Mol. Genet. 25, 5046–5058 (2016).
pubmed: 28171565
Cohen, S. P., Vase, L. & Hooten, W. M. Chronic pain: an update on burden, best practices, and new advances. Lancet 397, 2082–2097 (2021).
pubmed: 34062143
doi: 10.1016/S0140-6736(21)00393-7
Kvaskoff, M. et al. Endometriosis: a high-risk population for major chronic diseases? Hum. Reprod. Update 21, 500–516 (2015).
pubmed: 25765863
pmcid: 4463000
doi: 10.1093/humupd/dmv013
Shafrir, A. L. et al. Co-occurrence of immune-mediated conditions and endometriosis among adolescents and adult women. Am. J. Reprod. Immunol. 86, e13404 (2021).
pubmed: 33583078
pmcid: 8243788
doi: 10.1111/aji.13404
Tapmeier, T. T. et al. Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis. Sci. Transl. Med. 13, eabd6469 (2021).
pubmed: 34433639
doi: 10.1126/scitranslmed.abd6469
Shigesi, N. et al. The association between endometriosis and autoimmune diseases: a systematic review and meta-analysis. Hum. Reprod. Update 25, 486–503 (2019).
pubmed: 31260048
pmcid: 6601386
doi: 10.1093/humupd/dmz014
McGonagle, D. & McDermott, M. F. A proposed classification of the immunological diseases. PLoS Med. 3, e297 (2006).
pubmed: 16942393
pmcid: 1564298
doi: 10.1371/journal.pmed.0030297
Parazzini, F., Progretto Menopausa Italia Study Group Menopausal status, hormone replacement therapy use and risk of self-reported physician-diagnosed osteoarthritis in women attending menopause clinics in Italy. Maturitas 46, 207–212 (2003).
pubmed: 14585523
doi: 10.1016/S0378-5122(03)00193-2
O’Mara, T. A., Spurdle, A. B. & Glubb, D. M., Endometrial Cancer Association Consortium Analysis of promoter-associated chromatin interactions reveals biologically relevant candidate target genes at endometrial cancer risk Loci. Cancers 11, 1440 (2019).
pubmed: 31561579
pmcid: 6826789
doi: 10.3390/cancers11101440
Genomes Project, C. et al. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012).
doi: 10.1038/nature11632
Genomes Project, C. et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).
doi: 10.1038/nature15393
McCarthy, S. et al. A reference panel of 64,976 haplotypes for genotype imputation. Nat. Genet. 48, 1279–1283 (2016).
pubmed: 27548312
pmcid: 5388176
doi: 10.1038/ng.3643
Jonsson, H. et al. Whole genome characterization of sequence diversity of 15,220 Icelanders. Sci. Data 4, 170115 (2017).
pubmed: 28933420
pmcid: 5607473
doi: 10.1038/sdata.2017.115
Mitt, M. et al. Improved imputation accuracy of rare and low-frequency variants using population-specific high-coverage WGS-based imputation reference panel. Eur. J. Hum. Genet. 25, 869–876 (2017).
pubmed: 28401899
pmcid: 5520064
doi: 10.1038/ejhg.2017.51
Cook, J. P., Mahajan, A. & Morris, A. P. Guidance for the utility of linear models in meta-analysis of genetic association studies of binary phenotypes. Eur. J. Hum. Genet. 25, 240–245 (2017).
pubmed: 27848946
doi: 10.1038/ejhg.2016.150
Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).
pubmed: 11315092
doi: 10.1111/j.0006-341X.1999.00997.x
Willer, C. J., Li, Y. & Abecasis, G. R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).
pubmed: 20616382
pmcid: 2922887
doi: 10.1093/bioinformatics/btq340
Magi, R., Lindgren, C. M. & Morris, A. P. Meta-analysis of sex-specific genome-wide association studies. Genet. Epidemiol. 34, 846–853 (2010).
pubmed: 21104887
pmcid: 3410525
doi: 10.1002/gepi.20540
Yang, J., Lee, S. H., Goddard, M. E. & Visscher, P. M. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011).
pubmed: 21167468
pmcid: 3014363
doi: 10.1016/j.ajhg.2010.11.011
Wang, H. et al. SKAP-55 regulates integrin adhesion and formation of T cell-APC conjugates. Nat. Immunol. 4, 366–374 (2003).
pubmed: 12652296
doi: 10.1038/ni913
Morris, A. P. et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat. Genet. 44, 981–990 (2012).
pubmed: 22885922
pmcid: 3442244
doi: 10.1038/ng.2383
Janssen, E. B., Rijkers, A. C., Hoppenbrouwers, K., Meuleman, C. & D’Hooghe, T. M. Prevalence of endometriosis diagnosed by laparoscopy in adolescents with dysmenorrhea or chronic pelvic pain: a systematic review. Hum. Reprod. Update 19, 570–582 (2013).
pubmed: 23727940
doi: 10.1093/humupd/dmt016
Zondervan, K. T., Cardon, L. R. & Kennedy, S. H. The genetic basis of endometriosis. Curr. Opin. Obstet. Gynecol. 13, 309–314 (2001).
pubmed: 11396656
doi: 10.1097/00001703-200106000-00011
Wakefield, J. A Bayesian measure of the probability of false discovery in genetic epidemiology studies. Am. J. Hum. Genet. 81, 208–227 (2007).
pubmed: 17668372
pmcid: 1950810
doi: 10.1086/519024
Wellcome Trust Case Control, C. et al. Bayesian refinement of association signals for 14 loci in 3 common diseases. Nat. Genet. 44, 1294–1301 (2012).
doi: 10.1038/ng.2435
Watanabe, K., Taskesen, E., van Bochoven, A. & Posthuma, D. Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 8, 1826 (2017).
pubmed: 29184056
pmcid: 5705698
doi: 10.1038/s41467-017-01261-5
O’Mara, T. A., Spurdle, A. B. & Glubb, D. M. Analysis of promoter-associated chromatin interactions reveals biologically relevant candidate target genes at endometrial cancer risk loci. Cancers 11, 1440 (2019).
pubmed: 31561579
pmcid: 6826789
doi: 10.3390/cancers11101440
Jain, A. & Tuteja, G. TissueEnrich: tissue-specific gene enrichment analysis. Bioinformatics 35, 1966–1967 (2019).
pubmed: 30346488
doi: 10.1093/bioinformatics/bty890
Uhlen, M. et al. Proteomics. Tissue-based map of the human proteome. Science 347, 1260419 (2015).
pubmed: 25613900
doi: 10.1126/science.1260419
Consortium, G. T. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).
doi: 10.1126/science.1262110
Fung, J. N. et al. The genetic regulation of transcription in human endometrial tissue. Hum. Reprod. 32, 893–904 (2017).
pubmed: 28177073
doi: 10.1093/humrep/dex006
Gamazon, E. R. et al. Using an atlas of gene regulation across 44 human tissues to inform complex disease- and trait-associated variation. Nat. Genet. 50, 956–967 (2018).
pubmed: 29955180
pmcid: 6248311
doi: 10.1038/s41588-018-0154-4
Consortium, G. T. et al. Genetic effects on gene expression across human tissues. Nature 550, 204–213 (2017).
doi: 10.1038/nature24277
Qi, T. et al. Identifying gene targets for brain-related traits using transcriptomic and methylomic data from blood. Nat. Commun. 9, 2282 (2018).
pubmed: 29891976
pmcid: 5995828
doi: 10.1038/s41467-018-04558-1
Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010).
pubmed: 19910308
doi: 10.1093/bioinformatics/btp616
Delaneau, O. et al. A complete tool set for molecular QTL discovery and analysis. Nat. Commun. 8, 15452 (2017).
pubmed: 28516912
pmcid: 5454369
doi: 10.1038/ncomms15452
Zhang, F. et al. OSCA: a tool for omic-data-based complex trait analysis. Genome Biol. 20, 107 (2019).
pubmed: 31138268
pmcid: 6537380
doi: 10.1186/s13059-019-1718-z
Eraslan, G. et al. Single-nucleus cross-tissue molecular reference maps toward understanding disease gene function. Science 376, eabl4290 (2022).
pubmed: 35549429
pmcid: 9383269
doi: 10.1126/science.abl4290
Gordon, M. L.T. forestplot: Advanced forest plot using ‘grid’ graphics. https://CRAN.R-project.org/package=forestplot (2017).
Hautakangas, H. et al. Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles. Nat. Genet. 54, 152–160 (2022).
pubmed: 35115687
pmcid: 8837554
doi: 10.1038/s41588-021-00990-0
Johnston, K. J. A. et al. Genome-wide association study of multisite chronic pain in UK Biobank. PLoS Genet. 15, e1008164 (2019).
pubmed: 31194737
pmcid: 6592570
doi: 10.1371/journal.pgen.1008164