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Stress-related genetic components in attention-deficit/hyperactivity disorder (ADHD): Effects of the SERPINA6 and SERPINA1 genetic markers in a family-based brazilian sample
SERPINA6 and SERPINA1 were recently identified as the main genes associated with plasma cortisol concentration in humans. Although dysregulation in the Hypothalamus–Pituitary-Adrenal (HPA) axis has been observed in Attention Deficit/Hyperactivity Disorder (ADHD), the molecular mechanisms underlying...
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| Published in: | Journal of psychiatric research 2022-05, Vol.149, p.1-9 |
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| creator | Carpena, Marina Xavier Sánchez-Luquez, Karen Yumaira Martins-Silva, Thais Santos, Thiago M Farias, Cid Pinheiro Leventhal, Daniel Gray Paschoal Berruti, Barbara Zeni, Cristian Patrick Schmitz, Marcelo Chazan, Rodrigo Hutz, Mara H. Salatino-Oliveira, Angélica Genro, Julia P. Rohde, Luis Augusto Tovo-Rodrigues, Luciana |
| description | SERPINA6 and SERPINA1 were recently identified as the main genes associated with plasma cortisol concentration in humans. Although dysregulation in the Hypothalamus–Pituitary-Adrenal (HPA) axis has been observed in Attention Deficit/Hyperactivity Disorder (ADHD), the molecular mechanisms underlying this relationship are still unclear. Evaluation of the SERPINA6/SERPINA1 gene cluster in ADHD may provide relevant information to uncover them. We tested the association between the SERPINA6/SERPINA1 locus, including 95 single nucleotide polymorphisms (SNPs), and ADHD, using data from a Brazilian clinical sample of 259 ADHD probands and their parents. The single SNP association was tested using binary logistic regression, and we performed Classification and Regression Tree (CART) analysis to evaluate genotype combinations' effects on ADHD susceptibility. We assessed SNPs’ regulatory effects through the Genotype-Tissue Expression (GTEx) v8 tool, and performed a complementary look-up analysis in the largest ADHD GWAS to date. There was a suggestive association between ADHD and eight variants located in the SERPINA6 region and one in the intergenic region between SERPINA6 and SERPINA1 after correction for multiple tests (p |
| doi_str_mv | 10.1016/j.jpsychires.2022.02.014 |
| format | article |
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•HPA axis dysregulation, stress response dysfunction share genetic component with ADHD.•SERPINA6 gene may be tied to ADHD and HPA dysregulation, stress response dysfunction.•Interaction of rs2144833 and rs10129500 may imply variants' cumulative effect on ADHD.•SERPINA6 SNPs' associations seem specific to ADHD, unhampered by anxiety comorbidity.</description><identifier>ISSN: 0022-3956</identifier><identifier>EISSN: 1879-1379</identifier><identifier>DOI: 10.1016/j.jpsychires.2022.02.014</identifier><identifier>PMID: 35217314</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>ADHD ; alpha 1-Antitrypsin - genetics ; Attention Deficit Disorder with Hyperactivity - genetics ; Brazil ; Cortisol ; Genetic Markers ; Genotype ; GWAS ; HPA axis Dysregulation ; Humans ; Hydrocortisone - metabolism ; Polymorphism, Single Nucleotide ; SERPINA6 ; Transcortin - genetics</subject><ispartof>Journal of psychiatric research, 2022-05, Vol.149, p.1-9</ispartof><rights>2022 Elsevier Ltd</rights><rights>Copyright © 2022 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c374t-4cd6a0577f916691a2156718efafb88786e1dc4a43a870745df0b688dc5e61e93</citedby><cites>FETCH-LOGICAL-c374t-4cd6a0577f916691a2156718efafb88786e1dc4a43a870745df0b688dc5e61e93</cites><orcidid>0000-0001-5229-5697 ; 0000-0001-9810-3929 ; 0000-0002-4690-5791 ; 0000-0002-4572-5297 ; 0000-0001-5049-2435 ; 0000-0002-8732-6059 ; 0000-0002-9734-2300 ; 0000-0001-8394-1559</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35217314$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Carpena, Marina Xavier</creatorcontrib><creatorcontrib>Sánchez-Luquez, Karen Yumaira</creatorcontrib><creatorcontrib>Martins-Silva, Thais</creatorcontrib><creatorcontrib>Santos, Thiago M</creatorcontrib><creatorcontrib>Farias, Cid Pinheiro</creatorcontrib><creatorcontrib>Leventhal, Daniel Gray Paschoal</creatorcontrib><creatorcontrib>Berruti, Barbara</creatorcontrib><creatorcontrib>Zeni, Cristian Patrick</creatorcontrib><creatorcontrib>Schmitz, Marcelo</creatorcontrib><creatorcontrib>Chazan, Rodrigo</creatorcontrib><creatorcontrib>Hutz, Mara H.</creatorcontrib><creatorcontrib>Salatino-Oliveira, Angélica</creatorcontrib><creatorcontrib>Genro, Julia P.</creatorcontrib><creatorcontrib>Rohde, Luis Augusto</creatorcontrib><creatorcontrib>Tovo-Rodrigues, Luciana</creatorcontrib><title>Stress-related genetic components in attention-deficit/hyperactivity disorder (ADHD): Effects of the SERPINA6 and SERPINA1 genetic markers in a family-based brazilian sample</title><title>Journal of psychiatric research</title><addtitle>J Psychiatr Res</addtitle><description>SERPINA6 and SERPINA1 were recently identified as the main genes associated with plasma cortisol concentration in humans. Although dysregulation in the Hypothalamus–Pituitary-Adrenal (HPA) axis has been observed in Attention Deficit/Hyperactivity Disorder (ADHD), the molecular mechanisms underlying this relationship are still unclear. Evaluation of the SERPINA6/SERPINA1 gene cluster in ADHD may provide relevant information to uncover them. We tested the association between the SERPINA6/SERPINA1 locus, including 95 single nucleotide polymorphisms (SNPs), and ADHD, using data from a Brazilian clinical sample of 259 ADHD probands and their parents. The single SNP association was tested using binary logistic regression, and we performed Classification and Regression Tree (CART) analysis to evaluate genotype combinations' effects on ADHD susceptibility. We assessed SNPs’ regulatory effects through the Genotype-Tissue Expression (GTEx) v8 tool, and performed a complementary look-up analysis in the largest ADHD GWAS to date. There was a suggestive association between ADHD and eight variants located in the SERPINA6 region and one in the intergenic region between SERPINA6 and SERPINA1 after correction for multiple tests (p < 0.032). CART analysis showed that the combined effects of genotype GG in rs2144833 and CC in rs10129500 were associated with ADHD (OR = 1.78; CI95% = 1.24–2.55). The GTEx assigned the SNPs as eQTLs for genes in different tissues, including SERPINA6, and the look-up analysis revealed two SNPs associated with ADHD. These results suggest a shared genetic component between cortisol levels and ADHD. HPA dysregulation/altered stress response in ADHD might be mediated by upregulation of corticosteroid binding globulin (CBG, encoded by SERPINA6) expression.
•HPA axis dysregulation, stress response dysfunction share genetic component with ADHD.•SERPINA6 gene may be tied to ADHD and HPA dysregulation, stress response dysfunction.•Interaction of rs2144833 and rs10129500 may imply variants' cumulative effect on ADHD.•SERPINA6 SNPs' associations seem specific to ADHD, unhampered by anxiety comorbidity.</description><subject>ADHD</subject><subject>alpha 1-Antitrypsin - genetics</subject><subject>Attention Deficit Disorder with Hyperactivity - genetics</subject><subject>Brazil</subject><subject>Cortisol</subject><subject>Genetic Markers</subject><subject>Genotype</subject><subject>GWAS</subject><subject>HPA axis Dysregulation</subject><subject>Humans</subject><subject>Hydrocortisone - metabolism</subject><subject>Polymorphism, Single Nucleotide</subject><subject>SERPINA6</subject><subject>Transcortin - genetics</subject><issn>0022-3956</issn><issn>1879-1379</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNqFUd1uFCEUJkZj1-orGC7rxWxhYIDxbm3Xtkmjxuo1YeHgss5fgW0yvpPvWJpt66XJSc454fvh5EMIU7KkhIrT3XI3pdluQ4S0rEldL0kpyl-gBVWyrSiT7Uu0IOWlYm0jjtCblHaEEFlT_hodsaamklG-QH9vctFIVYTOZHD4FwyQg8V27KdxgCEnHAZsci5jGIfKgQ825NPtPEE0Noe7kGfsQhqjg4hPVueX5x8-4rX3YAt39DhvAd-sv3-7-rIS2AzuaaHPXr2JvyEejLA3fejmamNS-c0mmj-hC2bAyfRTB2_RK2-6BO8e-zH6-Xn94-yyuv56cXW2uq4skzxX3DphSCOlb6kQLTU1bYSkCrzxG6WkEkCd5YYzoySRvHGebIRSzjYgKLTsGJ0cdKc43u4hZd2HZKHrzADjPulaMKYawSUrUHWA2jimFMHrKYZy0awp0Q9h6Z3-F5Z-CEuTUpQX6vtHl_2mB_dMfEqnAD4dAFBuvQsQdbIBBguuaNms3Rj-73IPDTSsqA</recordid><startdate>202205</startdate><enddate>202205</enddate><creator>Carpena, Marina Xavier</creator><creator>Sánchez-Luquez, Karen Yumaira</creator><creator>Martins-Silva, Thais</creator><creator>Santos, Thiago M</creator><creator>Farias, Cid Pinheiro</creator><creator>Leventhal, Daniel Gray Paschoal</creator><creator>Berruti, Barbara</creator><creator>Zeni, Cristian Patrick</creator><creator>Schmitz, Marcelo</creator><creator>Chazan, Rodrigo</creator><creator>Hutz, Mara H.</creator><creator>Salatino-Oliveira, Angélica</creator><creator>Genro, Julia P.</creator><creator>Rohde, Luis Augusto</creator><creator>Tovo-Rodrigues, Luciana</creator><general>Elsevier Ltd</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>7X8</scope><orcidid>https://orcid.org/0000-0001-5229-5697</orcidid><orcidid>https://orcid.org/0000-0001-9810-3929</orcidid><orcidid>https://orcid.org/0000-0002-4690-5791</orcidid><orcidid>https://orcid.org/0000-0002-4572-5297</orcidid><orcidid>https://orcid.org/0000-0001-5049-2435</orcidid><orcidid>https://orcid.org/0000-0002-8732-6059</orcidid><orcidid>https://orcid.org/0000-0002-9734-2300</orcidid><orcidid>https://orcid.org/0000-0001-8394-1559</orcidid></search><sort><creationdate>202205</creationdate><title>Stress-related genetic components in attention-deficit/hyperactivity disorder (ADHD): Effects of the SERPINA6 and SERPINA1 genetic markers in a family-based brazilian sample</title><author>Carpena, Marina Xavier ; Sánchez-Luquez, Karen Yumaira ; Martins-Silva, Thais ; Santos, Thiago M ; Farias, Cid Pinheiro ; Leventhal, Daniel Gray Paschoal ; Berruti, Barbara ; Zeni, Cristian Patrick ; Schmitz, Marcelo ; Chazan, Rodrigo ; Hutz, Mara H. ; Salatino-Oliveira, Angélica ; Genro, Julia P. ; Rohde, Luis Augusto ; Tovo-Rodrigues, Luciana</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c374t-4cd6a0577f916691a2156718efafb88786e1dc4a43a870745df0b688dc5e61e93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>ADHD</topic><topic>alpha 1-Antitrypsin - genetics</topic><topic>Attention Deficit Disorder with Hyperactivity - genetics</topic><topic>Brazil</topic><topic>Cortisol</topic><topic>Genetic Markers</topic><topic>Genotype</topic><topic>GWAS</topic><topic>HPA axis Dysregulation</topic><topic>Humans</topic><topic>Hydrocortisone - metabolism</topic><topic>Polymorphism, Single Nucleotide</topic><topic>SERPINA6</topic><topic>Transcortin - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Carpena, Marina Xavier</creatorcontrib><creatorcontrib>Sánchez-Luquez, Karen Yumaira</creatorcontrib><creatorcontrib>Martins-Silva, Thais</creatorcontrib><creatorcontrib>Santos, Thiago M</creatorcontrib><creatorcontrib>Farias, Cid Pinheiro</creatorcontrib><creatorcontrib>Leventhal, Daniel Gray Paschoal</creatorcontrib><creatorcontrib>Berruti, Barbara</creatorcontrib><creatorcontrib>Zeni, Cristian Patrick</creatorcontrib><creatorcontrib>Schmitz, Marcelo</creatorcontrib><creatorcontrib>Chazan, Rodrigo</creatorcontrib><creatorcontrib>Hutz, Mara H.</creatorcontrib><creatorcontrib>Salatino-Oliveira, Angélica</creatorcontrib><creatorcontrib>Genro, Julia P.</creatorcontrib><creatorcontrib>Rohde, Luis Augusto</creatorcontrib><creatorcontrib>Tovo-Rodrigues, Luciana</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of psychiatric research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Carpena, Marina Xavier</au><au>Sánchez-Luquez, Karen Yumaira</au><au>Martins-Silva, Thais</au><au>Santos, Thiago M</au><au>Farias, Cid Pinheiro</au><au>Leventhal, Daniel Gray Paschoal</au><au>Berruti, Barbara</au><au>Zeni, Cristian Patrick</au><au>Schmitz, Marcelo</au><au>Chazan, Rodrigo</au><au>Hutz, Mara H.</au><au>Salatino-Oliveira, Angélica</au><au>Genro, Julia P.</au><au>Rohde, Luis Augusto</au><au>Tovo-Rodrigues, Luciana</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Stress-related genetic components in attention-deficit/hyperactivity disorder (ADHD): Effects of the SERPINA6 and SERPINA1 genetic markers in a family-based brazilian sample</atitle><jtitle>Journal of psychiatric research</jtitle><addtitle>J Psychiatr Res</addtitle><date>2022-05</date><risdate>2022</risdate><volume>149</volume><spage>1</spage><epage>9</epage><pages>1-9</pages><issn>0022-3956</issn><eissn>1879-1379</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>SERPINA6 and SERPINA1 were recently identified as the main genes associated with plasma cortisol concentration in humans. Although dysregulation in the Hypothalamus–Pituitary-Adrenal (HPA) axis has been observed in Attention Deficit/Hyperactivity Disorder (ADHD), the molecular mechanisms underlying this relationship are still unclear. Evaluation of the SERPINA6/SERPINA1 gene cluster in ADHD may provide relevant information to uncover them. We tested the association between the SERPINA6/SERPINA1 locus, including 95 single nucleotide polymorphisms (SNPs), and ADHD, using data from a Brazilian clinical sample of 259 ADHD probands and their parents. The single SNP association was tested using binary logistic regression, and we performed Classification and Regression Tree (CART) analysis to evaluate genotype combinations' effects on ADHD susceptibility. We assessed SNPs’ regulatory effects through the Genotype-Tissue Expression (GTEx) v8 tool, and performed a complementary look-up analysis in the largest ADHD GWAS to date. There was a suggestive association between ADHD and eight variants located in the SERPINA6 region and one in the intergenic region between SERPINA6 and SERPINA1 after correction for multiple tests (p < 0.032). CART analysis showed that the combined effects of genotype GG in rs2144833 and CC in rs10129500 were associated with ADHD (OR = 1.78; CI95% = 1.24–2.55). The GTEx assigned the SNPs as eQTLs for genes in different tissues, including SERPINA6, and the look-up analysis revealed two SNPs associated with ADHD. These results suggest a shared genetic component between cortisol levels and ADHD. HPA dysregulation/altered stress response in ADHD might be mediated by upregulation of corticosteroid binding globulin (CBG, encoded by SERPINA6) expression.
•HPA axis dysregulation, stress response dysfunction share genetic component with ADHD.•SERPINA6 gene may be tied to ADHD and HPA dysregulation, stress response dysfunction.•Interaction of rs2144833 and rs10129500 may imply variants' cumulative effect on ADHD.•SERPINA6 SNPs' associations seem specific to ADHD, unhampered by anxiety comorbidity.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>35217314</pmid><doi>10.1016/j.jpsychires.2022.02.014</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0001-5229-5697</orcidid><orcidid>https://orcid.org/0000-0001-9810-3929</orcidid><orcidid>https://orcid.org/0000-0002-4690-5791</orcidid><orcidid>https://orcid.org/0000-0002-4572-5297</orcidid><orcidid>https://orcid.org/0000-0001-5049-2435</orcidid><orcidid>https://orcid.org/0000-0002-8732-6059</orcidid><orcidid>https://orcid.org/0000-0002-9734-2300</orcidid><orcidid>https://orcid.org/0000-0001-8394-1559</orcidid></addata></record> |
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| ispartof | Journal of psychiatric research, 2022-05, Vol.149, p.1-9 |
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| source | ScienceDirect Freedom Collection |
| subjects | ADHD alpha 1-Antitrypsin - genetics Attention Deficit Disorder with Hyperactivity - genetics Brazil Cortisol Genetic Markers Genotype GWAS HPA axis Dysregulation Humans Hydrocortisone - metabolism Polymorphism, Single Nucleotide SERPINA6 Transcortin - genetics |
| title | Stress-related genetic components in attention-deficit/hyperactivity disorder (ADHD): Effects of the SERPINA6 and SERPINA1 genetic markers in a family-based brazilian sample |
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