Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder: association to overlapping traits in ADHD and autism
Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) often co-occur. Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance is esse...
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| description | Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) often co-occur. Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance is essential for proper brain development and functioning. In this study we investigated the role of glutamate and GABA genetics in ADHD severity, autism symptom severity and inhibitory performance, based on gene set analysis, an approach to investigate multiple genetic variants simultaneously. Common variants within glutamatergic and GABAergic genes were investigated using the MAGMA software in an ADHD case-only sample (
n
=931), in which we assessed ASD symptoms and response inhibition on a Stop task. Gene set analysis for ADHD symptom severity, divided into inattention and hyperactivity/impulsivity symptoms, autism symptom severity and inhibition were performed using principal component regression analyses. Subsequently, gene-wide association analyses were performed. The glutamate gene set showed an association with severity of hyperactivity/impulsivity (
P
=0.009), which was robust to correcting for genome-wide association levels. The GABA gene set showed nominally significant association with inhibition (
P
=0.04), but this did not survive correction for multiple comparisons. None of single gene or single variant associations was significant on their own. By analyzing multiple genetic variants within candidate gene sets together, we were able to find genetic associations supporting the involvement of excitatory and inhibitory neurotransmitter systems in ADHD and ASD symptom severity in ADHD. |
| doi_str_mv | 10.1038/tp.2016.273 |
| format | Article |
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n
=931), in which we assessed ASD symptoms and response inhibition on a Stop task. Gene set analysis for ADHD symptom severity, divided into inattention and hyperactivity/impulsivity symptoms, autism symptom severity and inhibition were performed using principal component regression analyses. Subsequently, gene-wide association analyses were performed. The glutamate gene set showed an association with severity of hyperactivity/impulsivity (
P
=0.009), which was robust to correcting for genome-wide association levels. The GABA gene set showed nominally significant association with inhibition (
P
=0.04), but this did not survive correction for multiple comparisons. None of single gene or single variant associations was significant on their own. By analyzing multiple genetic variants within candidate gene sets together, we were able to find genetic associations supporting the involvement of excitatory and inhibitory neurotransmitter systems in ADHD and ASD symptom severity in ADHD.</description><identifier>ISSN: 2158-3188</identifier><identifier>EISSN: 2158-3188</identifier><identifier>DOI: 10.1038/tp.2016.273</identifier><identifier>PMID: 28072412</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>692/699/476/1311 ; 692/699/476/1373 ; Adolescent ; Amino Acid Transport System y+L ; Attention Deficit Disorder with Hyperactivity - genetics ; Attention Deficit Disorder with Hyperactivity - metabolism ; Attention Deficit Disorder with Hyperactivity - psychology ; Autism Spectrum Disorder - genetics ; Autism Spectrum Disorder - metabolism ; Autism Spectrum Disorder - psychology ; Autistic Disorder - genetics ; Autistic Disorder - metabolism ; Autistic Disorder - psychology ; Behavioral Sciences ; Biological Psychology ; Calcium-Binding Proteins - genetics ; Child ; Child, Preschool ; Female ; Fusion Regulatory Protein 1, Light Chains ; gamma-Aminobutyric Acid - metabolism ; Glutamic Acid - metabolism ; Humans ; Male ; Medicine ; Medicine & Public Health ; Nerve Tissue Proteins - genetics ; Neurosciences ; Original ; original-article ; Pharmacotherapy ; Psychiatry ; Receptors, AMPA - genetics ; Receptors, GABA-A - genetics ; Receptors, Metabotropic Glutamate - genetics ; Receptors, N-Methyl-D-Aspartate - genetics ; Severity of Illness Index</subject><ispartof>Translational psychiatry, 2017-01, Vol.7 (1), p.e999-e999</ispartof><rights>The Author(s) 2017</rights><rights>Copyright Nature Publishing Group Jan 2017</rights><rights>Copyright © 2017 The Author(s) 2017 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c512t-4720ec3f9e262885444125c665bdcfd1080fa6027d6e00595c89a87003b7e2f83</citedby><cites>FETCH-LOGICAL-c512t-4720ec3f9e262885444125c665bdcfd1080fa6027d6e00595c89a87003b7e2f83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545734/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5545734/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28072412$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Naaijen, J</creatorcontrib><creatorcontrib>Bralten, J</creatorcontrib><creatorcontrib>Poelmans, G</creatorcontrib><creatorcontrib>Glennon, J C</creatorcontrib><creatorcontrib>Franke, B</creatorcontrib><creatorcontrib>Buitelaar, J K</creatorcontrib><creatorcontrib>IMAGE consortium</creatorcontrib><creatorcontrib>The IMAGE consortium</creatorcontrib><title>Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder: association to overlapping traits in ADHD and autism</title><title>Translational psychiatry</title><addtitle>Transl Psychiatry</addtitle><addtitle>Transl Psychiatry</addtitle><description>Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) often co-occur. Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance is essential for proper brain development and functioning. In this study we investigated the role of glutamate and GABA genetics in ADHD severity, autism symptom severity and inhibitory performance, based on gene set analysis, an approach to investigate multiple genetic variants simultaneously. Common variants within glutamatergic and GABAergic genes were investigated using the MAGMA software in an ADHD case-only sample (
n
=931), in which we assessed ASD symptoms and response inhibition on a Stop task. Gene set analysis for ADHD symptom severity, divided into inattention and hyperactivity/impulsivity symptoms, autism symptom severity and inhibition were performed using principal component regression analyses. Subsequently, gene-wide association analyses were performed. The glutamate gene set showed an association with severity of hyperactivity/impulsivity (
P
=0.009), which was robust to correcting for genome-wide association levels. The GABA gene set showed nominally significant association with inhibition (
P
=0.04), but this did not survive correction for multiple comparisons. None of single gene or single variant associations was significant on their own. By analyzing multiple genetic variants within candidate gene sets together, we were able to find genetic associations supporting the involvement of excitatory and inhibitory neurotransmitter systems in ADHD and ASD symptom severity in ADHD.</description><subject>692/699/476/1311</subject><subject>692/699/476/1373</subject><subject>Adolescent</subject><subject>Amino Acid Transport System y+L</subject><subject>Attention Deficit Disorder with Hyperactivity - genetics</subject><subject>Attention Deficit Disorder with Hyperactivity - metabolism</subject><subject>Attention Deficit Disorder with Hyperactivity - psychology</subject><subject>Autism Spectrum Disorder - genetics</subject><subject>Autism Spectrum Disorder - metabolism</subject><subject>Autism Spectrum Disorder - psychology</subject><subject>Autistic Disorder - genetics</subject><subject>Autistic Disorder - metabolism</subject><subject>Autistic Disorder - psychology</subject><subject>Behavioral Sciences</subject><subject>Biological Psychology</subject><subject>Calcium-Binding Proteins - genetics</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Female</subject><subject>Fusion Regulatory Protein 1, Light Chains</subject><subject>gamma-Aminobutyric Acid - metabolism</subject><subject>Glutamic Acid - metabolism</subject><subject>Humans</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Neurosciences</subject><subject>Original</subject><subject>original-article</subject><subject>Pharmacotherapy</subject><subject>Psychiatry</subject><subject>Receptors, AMPA - genetics</subject><subject>Receptors, GABA-A - genetics</subject><subject>Receptors, Metabotropic Glutamate - genetics</subject><subject>Receptors, N-Methyl-D-Aspartate - genetics</subject><subject>Severity of Illness Index</subject><issn>2158-3188</issn><issn>2158-3188</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNptkUFv1DAQhS0EolXpiTuyxAUJsrWdOHY4VFpa2CJV4gJny-tMUleJHWxnpf0F_G28TakWhC_j0Xx6M08PodeUrCgp5UWaVozQesVE-QydMsplUVIpnx_9T9B5jPckP15JKuhLdMIkEayi7BT92gxz0qNOEHprsHYt3qw_rZeuBwc4QorYOqxTApesd0ULnTU2XdztJwjaJLuzaY9bG31oIXzEOkZvrD6wOHnsdxAGPU3W9TgFbRe59fXN9cM6PScbx1foRaeHCOeP9Qz9-PL5-9VNcftt8_VqfVsYTlkqKsEImLJrgNVMSl5V2QU3dc23relaSiTpdE2YaGvIfhtuZKOlIKTcCmCdLM_Q5aI7zdsRWpMtBT2oKdhRh73y2qq_J87eqd7vFOcVF2WVBd49CgT_c4aY1GijgWHQDvwcFZUZE5Q2LKNv_0Hv_RxctvdAVawWosnU-4UywccYoHs6hhJ1yFilSR0yVjnjTL85vv-J_ZNoBj4sQMwj10M4Wvofvd9XjLHe</recordid><startdate>20170110</startdate><enddate>20170110</enddate><creator>Naaijen, J</creator><creator>Bralten, J</creator><creator>Poelmans, G</creator><creator>Glennon, J C</creator><creator>Franke, B</creator><creator>Buitelaar, J K</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><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>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170110</creationdate><title>Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder: association to overlapping traits in ADHD and autism</title><author>Naaijen, J ; 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Both are highly heritable; however, it has been difficult to discover genetic risk variants. Glutamate and GABA are main excitatory and inhibitory neurotransmitters in the brain; their balance is essential for proper brain development and functioning. In this study we investigated the role of glutamate and GABA genetics in ADHD severity, autism symptom severity and inhibitory performance, based on gene set analysis, an approach to investigate multiple genetic variants simultaneously. Common variants within glutamatergic and GABAergic genes were investigated using the MAGMA software in an ADHD case-only sample (
n
=931), in which we assessed ASD symptoms and response inhibition on a Stop task. Gene set analysis for ADHD symptom severity, divided into inattention and hyperactivity/impulsivity symptoms, autism symptom severity and inhibition were performed using principal component regression analyses. Subsequently, gene-wide association analyses were performed. The glutamate gene set showed an association with severity of hyperactivity/impulsivity (
P
=0.009), which was robust to correcting for genome-wide association levels. The GABA gene set showed nominally significant association with inhibition (
P
=0.04), but this did not survive correction for multiple comparisons. None of single gene or single variant associations was significant on their own. By analyzing multiple genetic variants within candidate gene sets together, we were able to find genetic associations supporting the involvement of excitatory and inhibitory neurotransmitter systems in ADHD and ASD symptom severity in ADHD.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28072412</pmid><doi>10.1038/tp.2016.273</doi><oa>free_for_read</oa></addata></record> |
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| subjects | 692/699/476/1311 692/699/476/1373 Adolescent Amino Acid Transport System y+L Attention Deficit Disorder with Hyperactivity - genetics Attention Deficit Disorder with Hyperactivity - metabolism Attention Deficit Disorder with Hyperactivity - psychology Autism Spectrum Disorder - genetics Autism Spectrum Disorder - metabolism Autism Spectrum Disorder - psychology Autistic Disorder - genetics Autistic Disorder - metabolism Autistic Disorder - psychology Behavioral Sciences Biological Psychology Calcium-Binding Proteins - genetics Child Child, Preschool Female Fusion Regulatory Protein 1, Light Chains gamma-Aminobutyric Acid - metabolism Glutamic Acid - metabolism Humans Male Medicine Medicine & Public Health Nerve Tissue Proteins - genetics Neurosciences Original original-article Pharmacotherapy Psychiatry Receptors, AMPA - genetics Receptors, GABA-A - genetics Receptors, Metabotropic Glutamate - genetics Receptors, N-Methyl-D-Aspartate - genetics Severity of Illness Index |
| title | Glutamatergic and GABAergic gene sets in attention-deficit/hyperactivity disorder: association to overlapping traits in ADHD and autism |
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