Genome-wide association study of blood lipids in Indians confirms universality of established variants
Lipids foster energy production and their altered levels have been coupled with metabolic ailments. Indians feature high prevalence of metabolic diseases, yet uncharacterized for genes regulating lipid homeostasis. We performed first GWAS for quantitative lipids (total cholesterol, LDL, HDL, and tri...
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| Veröffentlicht in: | Journal of human genetics 2019-06, Vol.64 (6), p.573-587 |
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| creator | Bandesh, Khushdeep Prasad, Gauri Giri, Anil K Kauser, Yasmeen Upadhyay, Medha Basu, Analabha Tandon, Nikhil Bharadwaj, Dwaipayan |
| description | Lipids foster energy production and their altered levels have been coupled with metabolic ailments. Indians feature high prevalence of metabolic diseases, yet uncharacterized for genes regulating lipid homeostasis. We performed first GWAS for quantitative lipids (total cholesterol, LDL, HDL, and triglycerides) exclusively in 5271 Indians. Further to corroborate our genetic findings, we investigated DNA methylation marks in peripheral blood in Indians at the identified loci (N = 233) and retrieved gene regulatory features from public domains. Recurrent GWAS loci-CELSR2, CETP, LPL, ZNF259, and BUD13 cropped up as lead signals in Indians, reflecting their universal applicability. Besides established variants, we found certain unreported variants at sub-genome-wide level-QKI, REEP3, TMCC2, FAM129C, FAM241B, and LOC100506207. These variants though failed to attain GWAS significance in Indians, but largely turned out to be active CpG sites in human subcutaneous adipose tissue and showed robust association to two or more lipid traits. Of which, QKI variants showed significant association to all four lipid traits and their designated region was observed to be a key gene regulatory segment denoting active transcription particularly in human subcutaneous adipose tissue. Both established and novel loci were observed to be significantly associated with altered DNA methylation in Indians for specific CpGs that resided in key regulatory elements. Further, gene-based association analysis pinpointed novel GWAS loci-LINC01340 and IQCJ-SCHIP1 for TC; IFT27, IFT88, and LINC02141 for HDL; and TEX26 for TG. Present study ascertains universality of selected known genes and also identifies certain novel loci for lipids in Indians by integrating data from various levels of gene regulation. |
| doi_str_mv | 10.1038/s10038-019-0591-7 |
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Indians feature high prevalence of metabolic diseases, yet uncharacterized for genes regulating lipid homeostasis. We performed first GWAS for quantitative lipids (total cholesterol, LDL, HDL, and triglycerides) exclusively in 5271 Indians. Further to corroborate our genetic findings, we investigated DNA methylation marks in peripheral blood in Indians at the identified loci (N = 233) and retrieved gene regulatory features from public domains. Recurrent GWAS loci-CELSR2, CETP, LPL, ZNF259, and BUD13 cropped up as lead signals in Indians, reflecting their universal applicability. Besides established variants, we found certain unreported variants at sub-genome-wide level-QKI, REEP3, TMCC2, FAM129C, FAM241B, and LOC100506207. These variants though failed to attain GWAS significance in Indians, but largely turned out to be active CpG sites in human subcutaneous adipose tissue and showed robust association to two or more lipid traits. Of which, QKI variants showed significant association to all four lipid traits and their designated region was observed to be a key gene regulatory segment denoting active transcription particularly in human subcutaneous adipose tissue. Both established and novel loci were observed to be significantly associated with altered DNA methylation in Indians for specific CpGs that resided in key regulatory elements. Further, gene-based association analysis pinpointed novel GWAS loci-LINC01340 and IQCJ-SCHIP1 for TC; IFT27, IFT88, and LINC02141 for HDL; and TEX26 for TG. Present study ascertains universality of selected known genes and also identifies certain novel loci for lipids in Indians by integrating data from various levels of gene regulation.</description><identifier>ISSN: 1434-5161</identifier><identifier>EISSN: 1435-232X</identifier><identifier>DOI: 10.1038/s10038-019-0591-7</identifier><identifier>PMID: 30911093</identifier><language>eng</language><publisher>England: Nature Publishing Group</publisher><subject>Adipose tissue ; Adult ; Asian Continental Ancestry Group - genetics ; Association analysis ; Cholesterol ; Cholesterol - blood ; Cholesterol - genetics ; Cholesterol, HDL - blood ; Cholesterol, HDL - genetics ; Cholesterol, LDL - blood ; Cholesterol, LDL - genetics ; CpG islands ; Deoxyribonucleic acid ; DNA ; DNA methylation ; DNA Methylation - genetics ; Female ; Gene regulation ; Genes ; Genome-wide association studies ; Genome-Wide Association Study ; Genomes ; High density lipoprotein ; Homeostasis ; Humans ; India - epidemiology ; Lipid Metabolism - genetics ; Lipids ; Lipids - blood ; Lipids - genetics ; Low density lipoprotein ; Male ; Metabolic disorders ; Metabolism ; Middle Aged ; Peripheral blood ; Polymorphism, Single Nucleotide - genetics ; Quantitative Trait Loci - genetics ; Regulatory sequences ; Subcutaneous Fat - growth & development ; Subcutaneous Fat - pathology ; Transcription ; Triglycerides ; Triglycerides - blood ; Triglycerides - genetics</subject><ispartof>Journal of human genetics, 2019-06, Vol.64 (6), p.573-587</ispartof><rights>2019© The Author(s), under exclusive licence to The Japan Society of Human Genetics 2019</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c353t-aa3ff08543c756f11c549c4889bfde9919fcf802b5a25ed323670b081453ad3a3</citedby><cites>FETCH-LOGICAL-c353t-aa3ff08543c756f11c549c4889bfde9919fcf802b5a25ed323670b081453ad3a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30911093$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bandesh, Khushdeep</creatorcontrib><creatorcontrib>Prasad, Gauri</creatorcontrib><creatorcontrib>Giri, Anil K</creatorcontrib><creatorcontrib>Kauser, Yasmeen</creatorcontrib><creatorcontrib>Upadhyay, Medha</creatorcontrib><creatorcontrib>Basu, Analabha</creatorcontrib><creatorcontrib>Tandon, Nikhil</creatorcontrib><creatorcontrib>Bharadwaj, Dwaipayan</creatorcontrib><creatorcontrib>INDICO</creatorcontrib><creatorcontrib>INDICO</creatorcontrib><title>Genome-wide association study of blood lipids in Indians confirms universality of established variants</title><title>Journal of human genetics</title><addtitle>J Hum Genet</addtitle><description>Lipids foster energy production and their altered levels have been coupled with metabolic ailments. Indians feature high prevalence of metabolic diseases, yet uncharacterized for genes regulating lipid homeostasis. We performed first GWAS for quantitative lipids (total cholesterol, LDL, HDL, and triglycerides) exclusively in 5271 Indians. Further to corroborate our genetic findings, we investigated DNA methylation marks in peripheral blood in Indians at the identified loci (N = 233) and retrieved gene regulatory features from public domains. Recurrent GWAS loci-CELSR2, CETP, LPL, ZNF259, and BUD13 cropped up as lead signals in Indians, reflecting their universal applicability. Besides established variants, we found certain unreported variants at sub-genome-wide level-QKI, REEP3, TMCC2, FAM129C, FAM241B, and LOC100506207. These variants though failed to attain GWAS significance in Indians, but largely turned out to be active CpG sites in human subcutaneous adipose tissue and showed robust association to two or more lipid traits. Of which, QKI variants showed significant association to all four lipid traits and their designated region was observed to be a key gene regulatory segment denoting active transcription particularly in human subcutaneous adipose tissue. Both established and novel loci were observed to be significantly associated with altered DNA methylation in Indians for specific CpGs that resided in key regulatory elements. Further, gene-based association analysis pinpointed novel GWAS loci-LINC01340 and IQCJ-SCHIP1 for TC; IFT27, IFT88, and LINC02141 for HDL; and TEX26 for TG. Present study ascertains universality of selected known genes and also identifies certain novel loci for lipids in Indians by integrating data from various levels of gene regulation.</description><subject>Adipose tissue</subject><subject>Adult</subject><subject>Asian Continental Ancestry Group - genetics</subject><subject>Association analysis</subject><subject>Cholesterol</subject><subject>Cholesterol - blood</subject><subject>Cholesterol - genetics</subject><subject>Cholesterol, HDL - blood</subject><subject>Cholesterol, HDL - genetics</subject><subject>Cholesterol, LDL - blood</subject><subject>Cholesterol, LDL - genetics</subject><subject>CpG islands</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>DNA Methylation - genetics</subject><subject>Female</subject><subject>Gene regulation</subject><subject>Genes</subject><subject>Genome-wide association studies</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>High density lipoprotein</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>India - epidemiology</subject><subject>Lipid Metabolism - genetics</subject><subject>Lipids</subject><subject>Lipids - blood</subject><subject>Lipids - genetics</subject><subject>Low density lipoprotein</subject><subject>Male</subject><subject>Metabolic disorders</subject><subject>Metabolism</subject><subject>Middle Aged</subject><subject>Peripheral blood</subject><subject>Polymorphism, Single Nucleotide - genetics</subject><subject>Quantitative Trait Loci - genetics</subject><subject>Regulatory sequences</subject><subject>Subcutaneous Fat - growth & development</subject><subject>Subcutaneous Fat - pathology</subject><subject>Transcription</subject><subject>Triglycerides</subject><subject>Triglycerides - blood</subject><subject>Triglycerides - genetics</subject><issn>1434-5161</issn><issn>1435-232X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNpdkc1LHTEUxYO01K_-Ad2UQDduUnOTyZvJskirgtBNC-5CJh8YmUlec2cU_3vje-qiq3MXv3M43EPIF-DfgcvhHIE3YRw040oD6w_IEXRSMSHF7Yfd3TEFGzgkx4j3vNGiF5_IoeQagGt5ROJlyGUO7DH5QC1icckuqWSKy-qfaIl0nErxdErb5JGmTK-zTzYjdSXHVGeka04PoaKd0rIzBFzsOCW8C54-2NrgBU_Jx2gnDJ9f9YT8_fXzz8UVu_l9eX3x44Y5qeTCrJUx8kF10vVqEwGc6rTrhkGP0QetQUcXBy5GZYUKXgq56fnIB-iUtF5aeULO9rnbWv6trYmZE7owTTaHsqIRoPtBd1zohn77D70va82tnRFCwLBDGwV7ytWCWEM025pmW58McPMygtmPYNoI5mUE0zfP19fkdZyDf3e8fV0-A1JQgsg</recordid><startdate>20190601</startdate><enddate>20190601</enddate><creator>Bandesh, Khushdeep</creator><creator>Prasad, Gauri</creator><creator>Giri, Anil K</creator><creator>Kauser, Yasmeen</creator><creator>Upadhyay, Medha</creator><creator>Basu, Analabha</creator><creator>Tandon, Nikhil</creator><creator>Bharadwaj, Dwaipayan</creator><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20190601</creationdate><title>Genome-wide association study of blood lipids in Indians confirms universality of established variants</title><author>Bandesh, Khushdeep ; Prasad, Gauri ; Giri, Anil K ; Kauser, Yasmeen ; Upadhyay, Medha ; Basu, Analabha ; Tandon, Nikhil ; Bharadwaj, Dwaipayan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-aa3ff08543c756f11c549c4889bfde9919fcf802b5a25ed323670b081453ad3a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adipose tissue</topic><topic>Adult</topic><topic>Asian Continental Ancestry Group - genetics</topic><topic>Association analysis</topic><topic>Cholesterol</topic><topic>Cholesterol - blood</topic><topic>Cholesterol - genetics</topic><topic>Cholesterol, HDL - blood</topic><topic>Cholesterol, HDL - genetics</topic><topic>Cholesterol, LDL - blood</topic><topic>Cholesterol, LDL - genetics</topic><topic>CpG islands</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA methylation</topic><topic>DNA Methylation - genetics</topic><topic>Female</topic><topic>Gene regulation</topic><topic>Genes</topic><topic>Genome-wide association studies</topic><topic>Genome-Wide Association Study</topic><topic>Genomes</topic><topic>High density lipoprotein</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>India - epidemiology</topic><topic>Lipid Metabolism - genetics</topic><topic>Lipids</topic><topic>Lipids - blood</topic><topic>Lipids - genetics</topic><topic>Low density lipoprotein</topic><topic>Male</topic><topic>Metabolic disorders</topic><topic>Metabolism</topic><topic>Middle Aged</topic><topic>Peripheral blood</topic><topic>Polymorphism, Single Nucleotide - genetics</topic><topic>Quantitative Trait Loci - genetics</topic><topic>Regulatory sequences</topic><topic>Subcutaneous Fat - growth & development</topic><topic>Subcutaneous Fat - pathology</topic><topic>Transcription</topic><topic>Triglycerides</topic><topic>Triglycerides - blood</topic><topic>Triglycerides - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bandesh, Khushdeep</creatorcontrib><creatorcontrib>Prasad, Gauri</creatorcontrib><creatorcontrib>Giri, Anil K</creatorcontrib><creatorcontrib>Kauser, Yasmeen</creatorcontrib><creatorcontrib>Upadhyay, Medha</creatorcontrib><creatorcontrib>Basu, Analabha</creatorcontrib><creatorcontrib>Tandon, Nikhil</creatorcontrib><creatorcontrib>Bharadwaj, Dwaipayan</creatorcontrib><creatorcontrib>INDICO</creatorcontrib><creatorcontrib>INDICO</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of human genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bandesh, Khushdeep</au><au>Prasad, Gauri</au><au>Giri, Anil K</au><au>Kauser, Yasmeen</au><au>Upadhyay, Medha</au><au>Basu, Analabha</au><au>Tandon, Nikhil</au><au>Bharadwaj, Dwaipayan</au><aucorp>INDICO</aucorp><aucorp>INDICO</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genome-wide association study of blood lipids in Indians confirms universality of established variants</atitle><jtitle>Journal of human genetics</jtitle><addtitle>J Hum Genet</addtitle><date>2019-06-01</date><risdate>2019</risdate><volume>64</volume><issue>6</issue><spage>573</spage><epage>587</epage><pages>573-587</pages><issn>1434-5161</issn><eissn>1435-232X</eissn><abstract>Lipids foster energy production and their altered levels have been coupled with metabolic ailments. Indians feature high prevalence of metabolic diseases, yet uncharacterized for genes regulating lipid homeostasis. We performed first GWAS for quantitative lipids (total cholesterol, LDL, HDL, and triglycerides) exclusively in 5271 Indians. Further to corroborate our genetic findings, we investigated DNA methylation marks in peripheral blood in Indians at the identified loci (N = 233) and retrieved gene regulatory features from public domains. Recurrent GWAS loci-CELSR2, CETP, LPL, ZNF259, and BUD13 cropped up as lead signals in Indians, reflecting their universal applicability. Besides established variants, we found certain unreported variants at sub-genome-wide level-QKI, REEP3, TMCC2, FAM129C, FAM241B, and LOC100506207. These variants though failed to attain GWAS significance in Indians, but largely turned out to be active CpG sites in human subcutaneous adipose tissue and showed robust association to two or more lipid traits. Of which, QKI variants showed significant association to all four lipid traits and their designated region was observed to be a key gene regulatory segment denoting active transcription particularly in human subcutaneous adipose tissue. Both established and novel loci were observed to be significantly associated with altered DNA methylation in Indians for specific CpGs that resided in key regulatory elements. Further, gene-based association analysis pinpointed novel GWAS loci-LINC01340 and IQCJ-SCHIP1 for TC; IFT27, IFT88, and LINC02141 for HDL; and TEX26 for TG. Present study ascertains universality of selected known genes and also identifies certain novel loci for lipids in Indians by integrating data from various levels of gene regulation.</abstract><cop>England</cop><pub>Nature Publishing Group</pub><pmid>30911093</pmid><doi>10.1038/s10038-019-0591-7</doi><tpages>15</tpages></addata></record> |
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| ispartof | Journal of human genetics, 2019-06, Vol.64 (6), p.573-587 |
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| subjects | Adipose tissue Adult Asian Continental Ancestry Group - genetics Association analysis Cholesterol Cholesterol - blood Cholesterol - genetics Cholesterol, HDL - blood Cholesterol, HDL - genetics Cholesterol, LDL - blood Cholesterol, LDL - genetics CpG islands Deoxyribonucleic acid DNA DNA methylation DNA Methylation - genetics Female Gene regulation Genes Genome-wide association studies Genome-Wide Association Study Genomes High density lipoprotein Homeostasis Humans India - epidemiology Lipid Metabolism - genetics Lipids Lipids - blood Lipids - genetics Low density lipoprotein Male Metabolic disorders Metabolism Middle Aged Peripheral blood Polymorphism, Single Nucleotide - genetics Quantitative Trait Loci - genetics Regulatory sequences Subcutaneous Fat - growth & development Subcutaneous Fat - pathology Transcription Triglycerides Triglycerides - blood Triglycerides - genetics |
| title | Genome-wide association study of blood lipids in Indians confirms universality of established variants |
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