Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders
Autism spectrum disorders (ASD) are heterogeneous disorders with a high heritability and complex genetic architecture. Due to the central role of the fragile X mental retardation gene 1 protein (FMRP) pathway in ASD we investigated common functional variants of ASD risk genes regulating FMRP. We gen...
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| Veröffentlicht in: | Human genetics 2014-06, Vol.133 (6), p.781-792 |
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| creator | Waltes, Regina Duketis, Eftichia Knapp, Michael Anney, Richard J. L. Huguet, Guillaume Schlitt, Sabine Jarczok, Tomasz A. Sachse, Michael Kämpfer, Laura M. Kleinböck, Tina Poustka, Fritz Bölte, Sven Schmötzer, Gabriele Voran, Anette Huy, Ellen Meyer, Jobst Bourgeron, Thomas Klauck, Sabine M. Freitag, Christine M. Chiocchetti, Andreas G. |
| description | Autism spectrum disorders (ASD) are heterogeneous disorders with a high heritability and complex genetic architecture. Due to the central role of the fragile X mental retardation gene 1 protein (FMRP) pathway in ASD we investigated common functional variants of ASD risk genes regulating FMRP. We genotyped ten SNPs in two German patient sets (
N
= 192 and
N
= 254 families, respectively) and report association for rs7170637 (
CYFIP1
; set 1 and combined sets), rs6923492 (
GRM1;
combined sets), and rs25925 (
CAMK4
; combined sets). An additional risk score based on variants with an odds ratio (OR) >1.25 in set 1 and weighted by their respective log transmitted/untransmitted ratio revealed a significant effect (OR 1.30, 95 % CI 1.11–1.53;
P
= 0.0013) in the combined German sample. A subsequent meta-analysis including the two German samples, the “Strict/European” ASD subsample of the Autism Genome Project (1,466 families) and a French case/control (541/366) cohort showed again association of rs7170637-A (OR 0.85, 95 % CI 0.75–0.96;
P
= 0.007) and rs25925-G (OR 1.31, 95 % CI 1.04–1.64;
P
= 0.021) with ASD. Functional analyses revealed that these minor alleles predicted to alter splicing factor binding sites significantly increase levels of an alternative mRNA isoform of the respective gene while keeping the overall expression of the gene constant. These findings underpin the role of ASD candidate genes in postsynaptic FMRP regulation suggesting that an imbalance of specific isoforms of
CYFIP1
, an FMRP interaction partner, and
CAMK4
, a transcriptional regulator of the FMRP gene, modulates ASD risk. Both gene products are related to neuronal regulation of synaptic plasticity, a pathomechanism underlying ASD and may thus present future targets for pharmacological therapies in ASD. |
| doi_str_mv | 10.1007/s00439-013-1416-y |
| format | Article |
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N
= 192 and
N
= 254 families, respectively) and report association for rs7170637 (
CYFIP1
; set 1 and combined sets), rs6923492 (
GRM1;
combined sets), and rs25925 (
CAMK4
; combined sets). An additional risk score based on variants with an odds ratio (OR) >1.25 in set 1 and weighted by their respective log transmitted/untransmitted ratio revealed a significant effect (OR 1.30, 95 % CI 1.11–1.53;
P
= 0.0013) in the combined German sample. A subsequent meta-analysis including the two German samples, the “Strict/European” ASD subsample of the Autism Genome Project (1,466 families) and a French case/control (541/366) cohort showed again association of rs7170637-A (OR 0.85, 95 % CI 0.75–0.96;
P
= 0.007) and rs25925-G (OR 1.31, 95 % CI 1.04–1.64;
P
= 0.021) with ASD. Functional analyses revealed that these minor alleles predicted to alter splicing factor binding sites significantly increase levels of an alternative mRNA isoform of the respective gene while keeping the overall expression of the gene constant. These findings underpin the role of ASD candidate genes in postsynaptic FMRP regulation suggesting that an imbalance of specific isoforms of
CYFIP1
, an FMRP interaction partner, and
CAMK4
, a transcriptional regulator of the FMRP gene, modulates ASD risk. Both gene products are related to neuronal regulation of synaptic plasticity, a pathomechanism underlying ASD and may thus present future targets for pharmacological therapies in ASD.</description><identifier>ISSN: 0340-6717</identifier><identifier>EISSN: 1432-1203</identifier><identifier>DOI: 10.1007/s00439-013-1416-y</identifier><identifier>PMID: 24442360</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Adaptor Proteins, Signal Transducing ; Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - metabolism ; Adolescent ; Alleles ; Autism ; Biomedical and Life Sciences ; Biomedicine ; Calcium-Calmodulin-Dependent Protein Kinase Type 4 ; Calcium-Calmodulin-Dependent Protein Kinase Type 4 - genetics ; Calcium-Calmodulin-Dependent Protein Kinase Type 4 - metabolism ; Child ; Child & adolescent psychiatry ; Child Development Disorders, Pervasive ; Child Development Disorders, Pervasive - ethnology ; Child Development Disorders, Pervasive - genetics ; Child Development Disorders, Pervasive - metabolism ; Child Development Disorders, Pervasive - pathology ; Child, Preschool ; Cognitive science ; European Continental Ancestry Group ; Family ; Female ; Fragile X Mental Retardation Protein ; Fragile X Mental Retardation Protein - genetics ; Fragile X Mental Retardation Protein - metabolism ; Gene Expression Regulation ; Gene Function ; Genes ; Genetic Predisposition to Disease ; Genetics ; Genomes ; Genomics ; Genotyping Techniques ; Human Genetics ; Human health and pathology ; Humans ; Intellectual disabilities ; Kinases ; Life Sciences ; Male ; Metabolic Diseases ; Molecular Medicine ; Neuronal Plasticity ; Neuronal Plasticity - genetics ; Original Investigation ; Polymorphism, Single Nucleotide ; Protein Binding ; Proteins ; Psychiatrics and mental health ; Risk Factors ; RNA ; Signal Transduction</subject><ispartof>Human genetics, 2014-06, Vol.133 (6), p.781-792</ispartof><rights>Springer-Verlag Berlin Heidelberg 2014</rights><rights>COPYRIGHT 2014 Springer</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c582t-d245544fd202e5355bb7d442b423b2a3bc84d8b3a4c671c2a0a782eae6bc15353</citedby><cites>FETCH-LOGICAL-c582t-d245544fd202e5355bb7d442b423b2a3bc84d8b3a4c671c2a0a782eae6bc15353</cites><orcidid>0000-0002-4746-6030 ; 0000-0001-8164-9220</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00439-013-1416-y$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00439-013-1416-y$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24442360$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://pasteur.hal.science/pasteur-01579800$$DView record in HAL$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:129040563$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Waltes, Regina</creatorcontrib><creatorcontrib>Duketis, Eftichia</creatorcontrib><creatorcontrib>Knapp, Michael</creatorcontrib><creatorcontrib>Anney, Richard J. L.</creatorcontrib><creatorcontrib>Huguet, Guillaume</creatorcontrib><creatorcontrib>Schlitt, Sabine</creatorcontrib><creatorcontrib>Jarczok, Tomasz A.</creatorcontrib><creatorcontrib>Sachse, Michael</creatorcontrib><creatorcontrib>Kämpfer, Laura M.</creatorcontrib><creatorcontrib>Kleinböck, Tina</creatorcontrib><creatorcontrib>Poustka, Fritz</creatorcontrib><creatorcontrib>Bölte, Sven</creatorcontrib><creatorcontrib>Schmötzer, Gabriele</creatorcontrib><creatorcontrib>Voran, Anette</creatorcontrib><creatorcontrib>Huy, Ellen</creatorcontrib><creatorcontrib>Meyer, Jobst</creatorcontrib><creatorcontrib>Bourgeron, Thomas</creatorcontrib><creatorcontrib>Klauck, Sabine M.</creatorcontrib><creatorcontrib>Freitag, Christine M.</creatorcontrib><creatorcontrib>Chiocchetti, Andreas G.</creatorcontrib><title>Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders</title><title>Human genetics</title><addtitle>Hum Genet</addtitle><addtitle>Hum Genet</addtitle><description>Autism spectrum disorders (ASD) are heterogeneous disorders with a high heritability and complex genetic architecture. Due to the central role of the fragile X mental retardation gene 1 protein (FMRP) pathway in ASD we investigated common functional variants of ASD risk genes regulating FMRP. We genotyped ten SNPs in two German patient sets (
N
= 192 and
N
= 254 families, respectively) and report association for rs7170637 (
CYFIP1
; set 1 and combined sets), rs6923492 (
GRM1;
combined sets), and rs25925 (
CAMK4
; combined sets). An additional risk score based on variants with an odds ratio (OR) >1.25 in set 1 and weighted by their respective log transmitted/untransmitted ratio revealed a significant effect (OR 1.30, 95 % CI 1.11–1.53;
P
= 0.0013) in the combined German sample. A subsequent meta-analysis including the two German samples, the “Strict/European” ASD subsample of the Autism Genome Project (1,466 families) and a French case/control (541/366) cohort showed again association of rs7170637-A (OR 0.85, 95 % CI 0.75–0.96;
P
= 0.007) and rs25925-G (OR 1.31, 95 % CI 1.04–1.64;
P
= 0.021) with ASD. Functional analyses revealed that these minor alleles predicted to alter splicing factor binding sites significantly increase levels of an alternative mRNA isoform of the respective gene while keeping the overall expression of the gene constant. These findings underpin the role of ASD candidate genes in postsynaptic FMRP regulation suggesting that an imbalance of specific isoforms of
CYFIP1
, an FMRP interaction partner, and
CAMK4
, a transcriptional regulator of the FMRP gene, modulates ASD risk. Both gene products are related to neuronal regulation of synaptic plasticity, a pathomechanism underlying ASD and may thus present future targets for pharmacological therapies in ASD.</description><subject>Adaptor Proteins, Signal Transducing</subject><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Adolescent</subject><subject>Alleles</subject><subject>Autism</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Calcium-Calmodulin-Dependent Protein Kinase Type 4</subject><subject>Calcium-Calmodulin-Dependent Protein Kinase Type 4 - genetics</subject><subject>Calcium-Calmodulin-Dependent Protein Kinase Type 4 - metabolism</subject><subject>Child</subject><subject>Child & adolescent psychiatry</subject><subject>Child Development Disorders, Pervasive</subject><subject>Child Development Disorders, Pervasive - ethnology</subject><subject>Child Development Disorders, Pervasive - genetics</subject><subject>Child Development Disorders, Pervasive - metabolism</subject><subject>Child Development Disorders, Pervasive - pathology</subject><subject>Child, Preschool</subject><subject>Cognitive science</subject><subject>European Continental Ancestry Group</subject><subject>Family</subject><subject>Female</subject><subject>Fragile X Mental Retardation Protein</subject><subject>Fragile X Mental Retardation Protein - genetics</subject><subject>Fragile X Mental Retardation Protein - metabolism</subject><subject>Gene Expression Regulation</subject><subject>Gene Function</subject><subject>Genes</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetics</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Genotyping Techniques</subject><subject>Human Genetics</subject><subject>Human health and pathology</subject><subject>Humans</subject><subject>Intellectual disabilities</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Metabolic Diseases</subject><subject>Molecular Medicine</subject><subject>Neuronal Plasticity</subject><subject>Neuronal Plasticity - genetics</subject><subject>Original Investigation</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>Psychiatrics and mental health</subject><subject>Risk Factors</subject><subject>RNA</subject><subject>Signal Transduction</subject><issn>0340-6717</issn><issn>1432-1203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkk1v1DAQhiMEoqXwA7ggS1zgkOKvbLLH1aqllRaBCpytieNk3SZ28Dgt--_xskvLIpCQD7bGz3y9M1n2ktFTRmn5DimVYp5TJnIm2SzfPMqOmRQ8Z5yKx9kxFZLms5KVR9kzxGtKWTHnxdPsiEspuZjR4wyXfhi8I7cQLLiIxDrSGWeQ-JbEtSGjx4gbB2O0mpx_uPpE0HYO-t66jowQ13ewIRAMCRZvSAs6-oCk9YHAFC0OBEejY5gG0lj0oTEBn2dPWujRvNjfJ9nX87Mvy4t89fH95XKxynVR8Zg3XBaFlG3DKTeFKIq6LptUd51KrzmIWleyqWoBUqceNQcKZcUNmFmtWeLFSZbv4uKdGadajcEOEDbKg1V70016GVVwyQv6wK-hP4AvFis1AkYzBZU0LOcVpbcs8W92_Bj8t8lgVINFbfoenPETqlSErHg1L-f_gfKi3E6qSujrP9BrP4Wk-E8qTbdilD9QHfRGWdf6GEBvg6qFKCkVKfk27elfqHQaM1jtnWltsh84vD1wSEw032MHE6K6_Hx1yLIdq4NHDKa914xRtd1PtdvPJJlQ2_1Um-Tzat_cVA-muff4tZAJ4PuZpS_XmfBb9_-M-gMJKu4Z</recordid><startdate>20140601</startdate><enddate>20140601</enddate><creator>Waltes, Regina</creator><creator>Duketis, Eftichia</creator><creator>Knapp, Michael</creator><creator>Anney, Richard J. L.</creator><creator>Huguet, Guillaume</creator><creator>Schlitt, Sabine</creator><creator>Jarczok, Tomasz A.</creator><creator>Sachse, Michael</creator><creator>Kämpfer, Laura M.</creator><creator>Kleinböck, Tina</creator><creator>Poustka, Fritz</creator><creator>Bölte, Sven</creator><creator>Schmötzer, Gabriele</creator><creator>Voran, Anette</creator><creator>Huy, Ellen</creator><creator>Meyer, Jobst</creator><creator>Bourgeron, Thomas</creator><creator>Klauck, Sabine M.</creator><creator>Freitag, Christine M.</creator><creator>Chiocchetti, Andreas G.</creator><general>Springer Berlin Heidelberg</general><general>Springer</general><general>Springer Nature B.V</general><general>Springer Verlag</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>ISR</scope><scope>3V.</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</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>PHGZM</scope><scope>PHGZT</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>RC3</scope><scope>7X8</scope><scope>1XC</scope><scope>ADTPV</scope><scope>AOWAS</scope><orcidid>https://orcid.org/0000-0002-4746-6030</orcidid><orcidid>https://orcid.org/0000-0001-8164-9220</orcidid></search><sort><creationdate>20140601</creationdate><title>Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders</title><author>Waltes, Regina ; Duketis, Eftichia ; Knapp, Michael ; Anney, Richard J. L. ; Huguet, Guillaume ; Schlitt, Sabine ; Jarczok, Tomasz A. ; Sachse, Michael ; Kämpfer, Laura M. ; Kleinböck, Tina ; Poustka, Fritz ; Bölte, Sven ; Schmötzer, Gabriele ; Voran, Anette ; Huy, Ellen ; Meyer, Jobst ; Bourgeron, Thomas ; Klauck, Sabine M. ; Freitag, Christine M. ; Chiocchetti, Andreas G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c582t-d245544fd202e5355bb7d442b423b2a3bc84d8b3a4c671c2a0a782eae6bc15353</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adaptor Proteins, Signal Transducing</topic><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Adolescent</topic><topic>Alleles</topic><topic>Autism</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Calcium-Calmodulin-Dependent Protein Kinase Type 4</topic><topic>Calcium-Calmodulin-Dependent Protein Kinase Type 4 - genetics</topic><topic>Calcium-Calmodulin-Dependent Protein Kinase Type 4 - metabolism</topic><topic>Child</topic><topic>Child & adolescent psychiatry</topic><topic>Child Development Disorders, Pervasive</topic><topic>Child Development Disorders, Pervasive - ethnology</topic><topic>Child Development Disorders, Pervasive - genetics</topic><topic>Child Development Disorders, Pervasive - metabolism</topic><topic>Child Development Disorders, Pervasive - pathology</topic><topic>Child, Preschool</topic><topic>Cognitive science</topic><topic>European Continental Ancestry Group</topic><topic>Family</topic><topic>Female</topic><topic>Fragile X Mental Retardation Protein</topic><topic>Fragile X Mental Retardation Protein - genetics</topic><topic>Fragile X Mental Retardation Protein - metabolism</topic><topic>Gene Expression Regulation</topic><topic>Gene Function</topic><topic>Genes</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetics</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Genotyping Techniques</topic><topic>Human Genetics</topic><topic>Human health and pathology</topic><topic>Humans</topic><topic>Intellectual disabilities</topic><topic>Kinases</topic><topic>Life Sciences</topic><topic>Male</topic><topic>Metabolic Diseases</topic><topic>Molecular Medicine</topic><topic>Neuronal Plasticity</topic><topic>Neuronal Plasticity - genetics</topic><topic>Original Investigation</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Protein Binding</topic><topic>Proteins</topic><topic>Psychiatrics and mental health</topic><topic>Risk Factors</topic><topic>RNA</topic><topic>Signal Transduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Waltes, Regina</creatorcontrib><creatorcontrib>Duketis, Eftichia</creatorcontrib><creatorcontrib>Knapp, Michael</creatorcontrib><creatorcontrib>Anney, Richard J. L.</creatorcontrib><creatorcontrib>Huguet, Guillaume</creatorcontrib><creatorcontrib>Schlitt, Sabine</creatorcontrib><creatorcontrib>Jarczok, Tomasz A.</creatorcontrib><creatorcontrib>Sachse, Michael</creatorcontrib><creatorcontrib>Kämpfer, Laura M.</creatorcontrib><creatorcontrib>Kleinböck, Tina</creatorcontrib><creatorcontrib>Poustka, Fritz</creatorcontrib><creatorcontrib>Bölte, Sven</creatorcontrib><creatorcontrib>Schmötzer, Gabriele</creatorcontrib><creatorcontrib>Voran, Anette</creatorcontrib><creatorcontrib>Huy, Ellen</creatorcontrib><creatorcontrib>Meyer, Jobst</creatorcontrib><creatorcontrib>Bourgeron, Thomas</creatorcontrib><creatorcontrib>Klauck, Sabine M.</creatorcontrib><creatorcontrib>Freitag, Christine M.</creatorcontrib><creatorcontrib>Chiocchetti, Andreas G.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</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 Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Applied & Life Sciences</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>SwePub</collection><collection>SwePub Articles</collection><jtitle>Human genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Waltes, Regina</au><au>Duketis, Eftichia</au><au>Knapp, Michael</au><au>Anney, Richard J. L.</au><au>Huguet, Guillaume</au><au>Schlitt, Sabine</au><au>Jarczok, Tomasz A.</au><au>Sachse, Michael</au><au>Kämpfer, Laura M.</au><au>Kleinböck, Tina</au><au>Poustka, Fritz</au><au>Bölte, Sven</au><au>Schmötzer, Gabriele</au><au>Voran, Anette</au><au>Huy, Ellen</au><au>Meyer, Jobst</au><au>Bourgeron, Thomas</au><au>Klauck, Sabine M.</au><au>Freitag, Christine M.</au><au>Chiocchetti, Andreas G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders</atitle><jtitle>Human genetics</jtitle><stitle>Hum Genet</stitle><addtitle>Hum Genet</addtitle><date>2014-06-01</date><risdate>2014</risdate><volume>133</volume><issue>6</issue><spage>781</spage><epage>792</epage><pages>781-792</pages><issn>0340-6717</issn><eissn>1432-1203</eissn><abstract>Autism spectrum disorders (ASD) are heterogeneous disorders with a high heritability and complex genetic architecture. Due to the central role of the fragile X mental retardation gene 1 protein (FMRP) pathway in ASD we investigated common functional variants of ASD risk genes regulating FMRP. We genotyped ten SNPs in two German patient sets (
N
= 192 and
N
= 254 families, respectively) and report association for rs7170637 (
CYFIP1
; set 1 and combined sets), rs6923492 (
GRM1;
combined sets), and rs25925 (
CAMK4
; combined sets). An additional risk score based on variants with an odds ratio (OR) >1.25 in set 1 and weighted by their respective log transmitted/untransmitted ratio revealed a significant effect (OR 1.30, 95 % CI 1.11–1.53;
P
= 0.0013) in the combined German sample. A subsequent meta-analysis including the two German samples, the “Strict/European” ASD subsample of the Autism Genome Project (1,466 families) and a French case/control (541/366) cohort showed again association of rs7170637-A (OR 0.85, 95 % CI 0.75–0.96;
P
= 0.007) and rs25925-G (OR 1.31, 95 % CI 1.04–1.64;
P
= 0.021) with ASD. Functional analyses revealed that these minor alleles predicted to alter splicing factor binding sites significantly increase levels of an alternative mRNA isoform of the respective gene while keeping the overall expression of the gene constant. These findings underpin the role of ASD candidate genes in postsynaptic FMRP regulation suggesting that an imbalance of specific isoforms of
CYFIP1
, an FMRP interaction partner, and
CAMK4
, a transcriptional regulator of the FMRP gene, modulates ASD risk. Both gene products are related to neuronal regulation of synaptic plasticity, a pathomechanism underlying ASD and may thus present future targets for pharmacological therapies in ASD.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>24442360</pmid><doi>10.1007/s00439-013-1416-y</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-4746-6030</orcidid><orcidid>https://orcid.org/0000-0001-8164-9220</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0340-6717 |
| ispartof | Human genetics, 2014-06, Vol.133 (6), p.781-792 |
| issn | 0340-6717 1432-1203 |
| language | eng |
| recordid | cdi_swepub_primary_oai_swepub_ki_se_524250 |
| source | MEDLINE; SpringerLink Journals |
| subjects | Adaptor Proteins, Signal Transducing Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Adolescent Alleles Autism Biomedical and Life Sciences Biomedicine Calcium-Calmodulin-Dependent Protein Kinase Type 4 Calcium-Calmodulin-Dependent Protein Kinase Type 4 - genetics Calcium-Calmodulin-Dependent Protein Kinase Type 4 - metabolism Child Child & adolescent psychiatry Child Development Disorders, Pervasive Child Development Disorders, Pervasive - ethnology Child Development Disorders, Pervasive - genetics Child Development Disorders, Pervasive - metabolism Child Development Disorders, Pervasive - pathology Child, Preschool Cognitive science European Continental Ancestry Group Family Female Fragile X Mental Retardation Protein Fragile X Mental Retardation Protein - genetics Fragile X Mental Retardation Protein - metabolism Gene Expression Regulation Gene Function Genes Genetic Predisposition to Disease Genetics Genomes Genomics Genotyping Techniques Human Genetics Human health and pathology Humans Intellectual disabilities Kinases Life Sciences Male Metabolic Diseases Molecular Medicine Neuronal Plasticity Neuronal Plasticity - genetics Original Investigation Polymorphism, Single Nucleotide Protein Binding Proteins Psychiatrics and mental health Risk Factors RNA Signal Transduction |
| title | Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-21T20%3A40%3A38IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_swepu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Common%20variants%20in%20genes%20of%20the%20postsynaptic%20FMRP%20signalling%20pathway%20are%20risk%20factors%20for%20autism%20spectrum%20disorders&rft.jtitle=Human%20genetics&rft.au=Waltes,%20Regina&rft.date=2014-06-01&rft.volume=133&rft.issue=6&rft.spage=781&rft.epage=792&rft.pages=781-792&rft.issn=0340-6717&rft.eissn=1432-1203&rft_id=info:doi/10.1007/s00439-013-1416-y&rft_dat=%3Cgale_swepu%3EA370031539%3C/gale_swepu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1524328102&rft_id=info:pmid/24442360&rft_galeid=A370031539&rfr_iscdi=true |