Family Clustering of Autoimmune Vitiligo Results Principally from Polygenic Inheritance of Common Risk Alleles
Vitiligo is an autoimmune disease that results in patches of depigmented skin and hair. Previous genome-wide association studies (GWASs) of vitiligo have identified 50 susceptibility loci. Variants at the associated loci are generally common and have individually small effects on risk. Most vitiligo...
Saved in:
| Published in: | American journal of human genetics Vol. 105; no. 2; p. 364 |
|---|---|
| Main Authors: | , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
01.08.2019
|
| Subjects: | |
| ISSN: | 1537-6605, 1537-6605 |
| Online Access: | Get more information |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Abstract | Vitiligo is an autoimmune disease that results in patches of depigmented skin and hair. Previous genome-wide association studies (GWASs) of vitiligo have identified 50 susceptibility loci. Variants at the associated loci are generally common and have individually small effects on risk. Most vitiligo cases are "simplex," where there is no family history of vitiligo, though occasional family clustering of vitiligo occurs, and some "multiplex" families report numerous close affected relatives. Here, we investigate whether simplex and multiplex vitiligo comprise different disease subtypes with different underlying genetic etiologies. We developed and compared the performance of several different vitiligo polygenic risk scores derived from GWAS data. By using the best-performing risk score, we find increased polygenic burden of risk alleles identified by GWAS in multiplex vitiligo cases relative to simplex cases. We additionally find evidence of polygenic transmission of common, low-effect-size risk alleles within multiplex-vitiligo-affected families. Our findings strongly suggest that family clustering of vitiligo involves a high burden of the same common, low-effect-size variants that are relevant in simplex cases. We furthermore find that a variant within the major histocompatibility complex (MHC) class II region contributes disproportionately more to risk in multiplex vitiligo cases than in simplex cases, supporting a special role for adaptive immune triggering in the etiology of multiplex cases. We suggest that genetic risk scores can be a useful tool in analyzing the genetic architecture of clinical disease subtypes and identifying subjects with unusual etiologies for further investigation. |
|---|---|
| AbstractList | Vitiligo is an autoimmune disease that results in patches of depigmented skin and hair. Previous genome-wide association studies (GWASs) of vitiligo have identified 50 susceptibility loci. Variants at the associated loci are generally common and have individually small effects on risk. Most vitiligo cases are "simplex," where there is no family history of vitiligo, though occasional family clustering of vitiligo occurs, and some "multiplex" families report numerous close affected relatives. Here, we investigate whether simplex and multiplex vitiligo comprise different disease subtypes with different underlying genetic etiologies. We developed and compared the performance of several different vitiligo polygenic risk scores derived from GWAS data. By using the best-performing risk score, we find increased polygenic burden of risk alleles identified by GWAS in multiplex vitiligo cases relative to simplex cases. We additionally find evidence of polygenic transmission of common, low-effect-size risk alleles within multiplex-vitiligo-affected families. Our findings strongly suggest that family clustering of vitiligo involves a high burden of the same common, low-effect-size variants that are relevant in simplex cases. We furthermore find that a variant within the major histocompatibility complex (MHC) class II region contributes disproportionately more to risk in multiplex vitiligo cases than in simplex cases, supporting a special role for adaptive immune triggering in the etiology of multiplex cases. We suggest that genetic risk scores can be a useful tool in analyzing the genetic architecture of clinical disease subtypes and identifying subjects with unusual etiologies for further investigation.Vitiligo is an autoimmune disease that results in patches of depigmented skin and hair. Previous genome-wide association studies (GWASs) of vitiligo have identified 50 susceptibility loci. Variants at the associated loci are generally common and have individually small effects on risk. Most vitiligo cases are "simplex," where there is no family history of vitiligo, though occasional family clustering of vitiligo occurs, and some "multiplex" families report numerous close affected relatives. Here, we investigate whether simplex and multiplex vitiligo comprise different disease subtypes with different underlying genetic etiologies. We developed and compared the performance of several different vitiligo polygenic risk scores derived from GWAS data. By using the best-performing risk score, we find increased polygenic burden of risk alleles identified by GWAS in multiplex vitiligo cases relative to simplex cases. We additionally find evidence of polygenic transmission of common, low-effect-size risk alleles within multiplex-vitiligo-affected families. Our findings strongly suggest that family clustering of vitiligo involves a high burden of the same common, low-effect-size variants that are relevant in simplex cases. We furthermore find that a variant within the major histocompatibility complex (MHC) class II region contributes disproportionately more to risk in multiplex vitiligo cases than in simplex cases, supporting a special role for adaptive immune triggering in the etiology of multiplex cases. We suggest that genetic risk scores can be a useful tool in analyzing the genetic architecture of clinical disease subtypes and identifying subjects with unusual etiologies for further investigation. Vitiligo is an autoimmune disease that results in patches of depigmented skin and hair. Previous genome-wide association studies (GWASs) of vitiligo have identified 50 susceptibility loci. Variants at the associated loci are generally common and have individually small effects on risk. Most vitiligo cases are "simplex," where there is no family history of vitiligo, though occasional family clustering of vitiligo occurs, and some "multiplex" families report numerous close affected relatives. Here, we investigate whether simplex and multiplex vitiligo comprise different disease subtypes with different underlying genetic etiologies. We developed and compared the performance of several different vitiligo polygenic risk scores derived from GWAS data. By using the best-performing risk score, we find increased polygenic burden of risk alleles identified by GWAS in multiplex vitiligo cases relative to simplex cases. We additionally find evidence of polygenic transmission of common, low-effect-size risk alleles within multiplex-vitiligo-affected families. Our findings strongly suggest that family clustering of vitiligo involves a high burden of the same common, low-effect-size variants that are relevant in simplex cases. We furthermore find that a variant within the major histocompatibility complex (MHC) class II region contributes disproportionately more to risk in multiplex vitiligo cases than in simplex cases, supporting a special role for adaptive immune triggering in the etiology of multiplex cases. We suggest that genetic risk scores can be a useful tool in analyzing the genetic architecture of clinical disease subtypes and identifying subjects with unusual etiologies for further investigation. |
| Author | Santorico, Stephanie A Yorgov, Daniel Paul, Subrata Spritz, Richard A Roberts, Genevieve H L |
| Author_xml | – sequence: 1 givenname: Genevieve H L surname: Roberts fullname: Roberts, Genevieve H L organization: Human Medical Genetics and Genomics Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA – sequence: 2 givenname: Subrata surname: Paul fullname: Paul, Subrata organization: Department of Mathematical and Statistical Sciences, University of Colorado Denver, Denver, CO 80217, USA – sequence: 3 givenname: Daniel surname: Yorgov fullname: Yorgov, Daniel organization: Department of Mathematical Sciences, Purdue University Fort Wayne, Fort Wayne, IN 46805, USA – sequence: 4 givenname: Stephanie A surname: Santorico fullname: Santorico, Stephanie A organization: Human Medical Genetics and Genomics Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Mathematical and Statistical Sciences, University of Colorado Denver, Denver, CO 80217, USA; Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado, Aurora, CO 80045, USA; Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA – sequence: 5 givenname: Richard A surname: Spritz fullname: Spritz, Richard A email: Richard.Spritz@ucdenver.edu organization: Human Medical Genetics and Genomics Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: Richard.Spritz@ucdenver.edu |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31327509$$D View this record in MEDLINE/PubMed |
| BookMark | eNpNkMtOwzAQRS1URB_wAyyQl2wSxnGcxMsqolCpElUFbCPXcVIXP0qcLPr3BAESqxmNzj3S3DmaOO8UQrcEYgIkezjG4nho4wQIjyGLgdALNCOM5lGWAZv826doHsIRgJAC6BWaUkKTnAGfIbcSVpszLs0QetVp12Lf4OXQe23t4BR-1702uvV4p8Jg-oC3IyT1SZgx1XTe4q0351Y5LfHaHUZFL5xU35bSW-sd3unwgZfGKKPCNbpshAnq5ncu0Nvq8bV8jjYvT-tyuYlkylgfsSxNij1ne0ZUAQUHmqvxAjQVIGoiCR1fgZRIXjOq6rEBWXBOM9rkKc8ZSxbo_sd76vznoEJfWR2kMkY45YdQJUlGeA5jYkTvftFhb1VdnTptRXeu_jpKvgAzAGsH |
| CitedBy_id | crossref_primary_10_1002_ca_24040 crossref_primary_10_1016_j_ajhg_2024_09_007 crossref_primary_10_1136_annrheumdis_2020_218558 crossref_primary_10_1016_j_jid_2020_06_004 crossref_primary_10_1111_exd_14100 crossref_primary_10_1111_pcmr_12848 crossref_primary_10_1007_s12016_021_08868_z crossref_primary_10_3390_nu17020357 crossref_primary_10_1093_hmg_ddaa005 crossref_primary_10_5937_jomb0_56661 crossref_primary_10_1146_annurev_immunol_100919_023531 crossref_primary_10_1093_bjd_ljad321 crossref_primary_10_1016_j_jid_2020_07_016 crossref_primary_10_3390_genes14051118 crossref_primary_10_1016_j_autrev_2020_102664 crossref_primary_10_1111_pcmr_13164 crossref_primary_10_3389_fimmu_2025_1543355 crossref_primary_10_1080_21655979_2021_1933743 crossref_primary_10_1111_1346_8138_15743 crossref_primary_10_1111_ijd_15852 crossref_primary_10_3389_fgene_2021_627092 |
| ContentType | Journal Article |
| Copyright | Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. |
| Copyright_xml | – notice: Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. |
| DBID | CGR CUY CVF ECM EIF NPM 7X8 |
| DOI | 10.1016/j.ajhg.2019.06.013 |
| DatabaseName | Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic |
| DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic |
| DatabaseTitleList | MEDLINE - Academic MEDLINE |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database |
| DeliveryMethod | no_fulltext_linktorsrc |
| Discipline | Biology |
| EISSN | 1537-6605 |
| ExternalDocumentID | 31327509 |
| Genre | Journal Article Research Support, N.I.H., Extramural |
| GrantInformation_xml | – fundername: NIAMS NIH HHS grantid: R01 AR045212 |
| GroupedDBID | --- --K --Z -~X 0R~ 123 1~5 23M 2WC 4.4 457 4G. 53G 5GY 62- 6J9 7-5 85S AAEDT AAEDW AAFWJ AAKRW AALRI AAMRU AAVLU AAWTL AAXUO ABDGV ABJNI ABMAC ABOCM ACGFO ACGFS ACGOD ACNCT ACPRK ACVFH ADBBV ADCNI ADEZE ADVLN AENEX AEUPX AEXQZ AFPUW AFRAH AFTJW AGCQF AGKMS AHMBA AIGII AITUG AKAPO AKBMS AKRWK AKYEP ALMA_UNASSIGNED_HOLDINGS AMRAJ AOIJS APXCP ASPBG AVWKF AZFZN BAWUL CGR CS3 CUY CVF D0L DIK E3Z EBS ECM ECV EFKBS EIF EJD F5P FCP FDB FEDTE GX1 HVGLF HYE IH2 IHE IXB JIG KQ8 L7B M41 NPM O-L O9- OK1 P2P PQQKQ RIG RNS ROL RPM RPZ SES SJN SSZ TN5 TR2 TWZ UHB UKR UNMZH UPT WH7 ZCA 7X8 |
| ID | FETCH-LOGICAL-c455t-56428b95b51e8089037e428034a0ad1c13011041c9d53ed201c899363f7497552 |
| IEDL.DBID | 7X8 |
| ISICitedReferencesCount | 26 |
| ISICitedReferencesURI | http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000478022200010&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| ISSN | 1537-6605 |
| IngestDate | Thu Oct 02 10:59:03 EDT 2025 Mon Jul 21 06:04:34 EDT 2025 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 2 |
| Keywords | genetic architecture vitiligo genetic risk score family clustering autoimmunity polygenic inheritance |
| Language | English |
| License | Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. |
| LinkModel | DirectLink |
| MergedId | FETCHMERGED-LOGICAL-c455t-56428b95b51e8089037e428034a0ad1c13011041c9d53ed201c899363f7497552 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| OpenAccessLink | http://www.cell.com/article/S0002929719302381/pdf |
| PMID | 31327509 |
| PQID | 2261970363 |
| PQPubID | 23479 |
| ParticipantIDs | proquest_miscellaneous_2261970363 pubmed_primary_31327509 |
| PublicationCentury | 2000 |
| PublicationDate | 2019-08-01 |
| PublicationDateYYYYMMDD | 2019-08-01 |
| PublicationDate_xml | – month: 08 year: 2019 text: 2019-08-01 day: 01 |
| PublicationDecade | 2010 |
| PublicationPlace | United States |
| PublicationPlace_xml | – name: United States |
| PublicationTitle | American journal of human genetics |
| PublicationTitleAlternate | Am J Hum Genet |
| PublicationYear | 2019 |
| SSID | ssj0011803 |
| Score | 2.432041 |
| Snippet | Vitiligo is an autoimmune disease that results in patches of depigmented skin and hair. Previous genome-wide association studies (GWASs) of vitiligo have... |
| SourceID | proquest pubmed |
| SourceType | Aggregation Database Index Database |
| StartPage | 364 |
| SubjectTerms | Alleles Autoimmune Diseases - genetics Autoimmune Diseases - pathology Case-Control Studies Family Female Genes - genetics Genetic Predisposition to Disease Genome-Wide Association Study Genotype Humans Male Multifactorial Inheritance Polymorphism, Single Nucleotide Risk Factors Vitiligo - genetics Vitiligo - pathology |
| Title | Family Clustering of Autoimmune Vitiligo Results Principally from Polygenic Inheritance of Common Risk Alleles |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/31327509 https://www.proquest.com/docview/2261970363 |
| Volume | 105 |
| WOSCitedRecordID | wos000478022200010&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D |
| hasFullText | |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1LS8QwEA7qKnjx_VhfRPBa7CNp0pMsi4seXMqisreSpulaLc1qW2H_vZm2y54EwUtvCelkMvNlMjMfQjd-SpRQqbS4JylEq2JjB5W0POkSwVjCXMUbsgk2HvPpNAi7gFvZpVUubWJjqBMtIUZ-6wLUb7pF3c0_LWCNgtfVjkJjHfU8A2VAq9l09Yrg8IYZ2RxqZvkGt3dFM21-l3h_m0FqV9D07wR6g98gZuNqRrv_XeQe2ulAJh60WrGP1lRxgLZa2snFISpatgs8zGtok2CcF9YpHtSVzqBaROHXrMrybKbxRJV1XpU4bEPyIjejoCAFhzpfGNXLJH4soIKwAuWBWaDgRBd4kpUfeJDnxqmVR-hldP88fLA63gVLEkori8KdJA5oTB3FbR7YHlMEWKyIsEXiSAeMgk0cGSTUU4mRoTS3NvPTKSMBo9Q9RhuFLtQpwq6UQWogiM8ZJzQ2s3qJr0SsnIQIFdt9dL0UZGT0Gh4rRKF0XUYrUfbRSbsb0bxtwBFBu0lAOmd_GH2OtmGT25y9C9RLzalWl2hTfldZ-XXVKIz5jsOnH2-0yqU |
| linkProvider | ProQuest |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Family+Clustering+of+Autoimmune+Vitiligo+Results+Principally+from+Polygenic+Inheritance+of+Common+Risk+Alleles&rft.jtitle=American+journal+of+human+genetics&rft.au=Roberts%2C+Genevieve+H+L&rft.au=Paul%2C+Subrata&rft.au=Yorgov%2C+Daniel&rft.au=Santorico%2C+Stephanie+A&rft.date=2019-08-01&rft.eissn=1537-6605&rft.volume=105&rft.issue=2&rft.spage=364&rft_id=info:doi/10.1016%2Fj.ajhg.2019.06.013&rft_id=info%3Apmid%2F31327509&rft_id=info%3Apmid%2F31327509&rft.externalDocID=31327509 |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1537-6605&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1537-6605&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1537-6605&client=summon |