Genetics of dementia in a Finnish cohort
Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two most common neurodegenerative dementias. Variants in APP, PSEN1 and PSEN2 are typically linked to early-onset AD, and several genetic risk loci are associated with late-onset AD. Inherited FTD can be caused by hexanucleotide...
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| Veröffentlicht in: | European journal of human genetics : EJHG 2018-06, Vol.26 (6), p.827-837 |
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| creator | Pasanen, Petra Myllykangas, Liisa Pöyhönen, Minna Kiviharju, Anna Siitonen, Maija Hardy, John Bras, Jose Paetau, Anders Tienari, Pentti J Guerreiro, Rita Verkkoniemi-Ahola, Auli |
| description | Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two most common neurodegenerative dementias. Variants in APP, PSEN1 and PSEN2 are typically linked to early-onset AD, and several genetic risk loci are associated with late-onset AD. Inherited FTD can be caused by hexanucleotide expansions in C9orf72, or variants in GRN, MAPT or CHMP2B. Several other genes have also been linked to FTD or FTD with motor neuron disease. Here we describe a cohort of 60 Finnish families with possible inherited dementia. Our aim was to clarify the genetic background of dementia in this cohort by analysing both known dementia-associated genes (APOE, APP, C9ORF72, GRN, PSEN1 and PSEN2) and searching for rare or novel segregating variants with exome sequencing. C9orf72 repeat expansions were detected in 12 (20%) of the 60 families, including, in addition to FTD, a family with neuropathologically verified AD. Twelve families (10 with AD and 2 with FTD) with representative samples from affected and unaffected subjects and without C9orf72 expansions were selected for whole-exome sequencing. Exome sequencing did not reveal any variants that could be regarded unequivocally causative, but revealed potentially damaging variants in UNC13C and MARCH4. |
| doi_str_mv | 10.1038/s41431-018-0117-3 |
| format | Article |
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Variants in APP, PSEN1 and PSEN2 are typically linked to early-onset AD, and several genetic risk loci are associated with late-onset AD. Inherited FTD can be caused by hexanucleotide expansions in C9orf72, or variants in GRN, MAPT or CHMP2B. Several other genes have also been linked to FTD or FTD with motor neuron disease. Here we describe a cohort of 60 Finnish families with possible inherited dementia. Our aim was to clarify the genetic background of dementia in this cohort by analysing both known dementia-associated genes (APOE, APP, C9ORF72, GRN, PSEN1 and PSEN2) and searching for rare or novel segregating variants with exome sequencing. C9orf72 repeat expansions were detected in 12 (20%) of the 60 families, including, in addition to FTD, a family with neuropathologically verified AD. Twelve families (10 with AD and 2 with FTD) with representative samples from affected and unaffected subjects and without C9orf72 expansions were selected for whole-exome sequencing. Exome sequencing did not reveal any variants that could be regarded unequivocally causative, but revealed potentially damaging variants in UNC13C and MARCH4.</description><identifier>ISSN: 1018-4813</identifier><identifier>EISSN: 1476-5438</identifier><identifier>DOI: 10.1038/s41431-018-0117-3</identifier><identifier>PMID: 29476165</identifier><language>eng</language><publisher>England: Nature Publishing Group</publisher><subject>Age ; Aged ; Alzheimer Disease - genetics ; Alzheimer Disease - pathology ; Alzheimer's disease ; Apolipoprotein E ; C9orf72 Protein - genetics ; Dementia ; Dementia disorders ; Female ; Frontotemporal dementia ; Frontotemporal Dementia - genetics ; Frontotemporal Dementia - pathology ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Motor neuron diseases ; Whole Exome Sequencing</subject><ispartof>European journal of human genetics : EJHG, 2018-06, Vol.26 (6), p.827-837</ispartof><rights>Copyright Nature Publishing Group Jun 2018</rights><rights>European Society of Human Genetics 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c427t-612512837e5d293cc6c0fb0c5b7db6b022b3e30356e2a50bdd0966233fa063c3</citedby><cites>FETCH-LOGICAL-c427t-612512837e5d293cc6c0fb0c5b7db6b022b3e30356e2a50bdd0966233fa063c3</cites><orcidid>0000-0003-2069-5877</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974394/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974394/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29476165$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pasanen, Petra</creatorcontrib><creatorcontrib>Myllykangas, Liisa</creatorcontrib><creatorcontrib>Pöyhönen, Minna</creatorcontrib><creatorcontrib>Kiviharju, Anna</creatorcontrib><creatorcontrib>Siitonen, Maija</creatorcontrib><creatorcontrib>Hardy, John</creatorcontrib><creatorcontrib>Bras, Jose</creatorcontrib><creatorcontrib>Paetau, Anders</creatorcontrib><creatorcontrib>Tienari, Pentti J</creatorcontrib><creatorcontrib>Guerreiro, Rita</creatorcontrib><creatorcontrib>Verkkoniemi-Ahola, Auli</creatorcontrib><title>Genetics of dementia in a Finnish cohort</title><title>European journal of human genetics : EJHG</title><addtitle>Eur J Hum Genet</addtitle><description>Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two most common neurodegenerative dementias. 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Exome sequencing did not reveal any variants that could be regarded unequivocally causative, but revealed potentially damaging variants in UNC13C and MARCH4.</description><subject>Age</subject><subject>Aged</subject><subject>Alzheimer Disease - genetics</subject><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer's disease</subject><subject>Apolipoprotein E</subject><subject>C9orf72 Protein - genetics</subject><subject>Dementia</subject><subject>Dementia disorders</subject><subject>Female</subject><subject>Frontotemporal dementia</subject><subject>Frontotemporal Dementia - genetics</subject><subject>Frontotemporal Dementia - pathology</subject><subject>Genetic Association Studies</subject><subject>Genetic Predisposition to Disease</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Motor neuron diseases</subject><subject>Whole Exome Sequencing</subject><issn>1018-4813</issn><issn>1476-5438</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNpdkUFLAzEQhYMotlZ_gBdZ8NLL6iSTZHcvghRbhYKX3kM2m7Up203d7Ar-e1OqRT2ECbxvHjPzCLmmcEcB8_vAKUeaAs3jo1mKJ2RMeSZTwTE_jf-9wnOKI3IRwgYgihk9JyNWRIpKMSbThW1t70xIfJ1Udmvb3unEtYlO5q5tXVgnxq9911-Ss1o3wV591wlZzZ9Ws-d0-bp4mT0uU8NZ1qeSMkFZjpkVFSvQGGmgLsGIMqtKWQJjJVoEFNIyLaCsKiikZIi1BokGJ-ThYLsbyq2tTJyn043adW6ru0_ltVN_ldat1Zv_UKLIOBY8Gky_DTr_PtjQq60LxjaNbq0fgmIAWZED8CKit__QjR-6Nm4XKS5FXoCgkaIHynQ-hM7Wx2EoqH0M6hCDisdW-xgUxp6b31scO37ujl_mXIEC</recordid><startdate>20180601</startdate><enddate>20180601</enddate><creator>Pasanen, Petra</creator><creator>Myllykangas, Liisa</creator><creator>Pöyhönen, Minna</creator><creator>Kiviharju, Anna</creator><creator>Siitonen, Maija</creator><creator>Hardy, John</creator><creator>Bras, Jose</creator><creator>Paetau, Anders</creator><creator>Tienari, Pentti J</creator><creator>Guerreiro, Rita</creator><creator>Verkkoniemi-Ahola, Auli</creator><general>Nature Publishing Group</general><general>Springer International Publishing</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>88A</scope><scope>88E</scope><scope>8AO</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><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2069-5877</orcidid></search><sort><creationdate>20180601</creationdate><title>Genetics of dementia in a Finnish cohort</title><author>Pasanen, Petra ; Myllykangas, Liisa ; Pöyhönen, Minna ; Kiviharju, Anna ; Siitonen, Maija ; Hardy, John ; Bras, Jose ; Paetau, Anders ; Tienari, Pentti J ; Guerreiro, Rita ; Verkkoniemi-Ahola, Auli</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c427t-612512837e5d293cc6c0fb0c5b7db6b022b3e30356e2a50bdd0966233fa063c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Age</topic><topic>Aged</topic><topic>Alzheimer Disease - 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Variants in APP, PSEN1 and PSEN2 are typically linked to early-onset AD, and several genetic risk loci are associated with late-onset AD. Inherited FTD can be caused by hexanucleotide expansions in C9orf72, or variants in GRN, MAPT or CHMP2B. Several other genes have also been linked to FTD or FTD with motor neuron disease. Here we describe a cohort of 60 Finnish families with possible inherited dementia. Our aim was to clarify the genetic background of dementia in this cohort by analysing both known dementia-associated genes (APOE, APP, C9ORF72, GRN, PSEN1 and PSEN2) and searching for rare or novel segregating variants with exome sequencing. C9orf72 repeat expansions were detected in 12 (20%) of the 60 families, including, in addition to FTD, a family with neuropathologically verified AD. Twelve families (10 with AD and 2 with FTD) with representative samples from affected and unaffected subjects and without C9orf72 expansions were selected for whole-exome sequencing. 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| source | MEDLINE; Springer Nature - Complete Springer Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Age Aged Alzheimer Disease - genetics Alzheimer Disease - pathology Alzheimer's disease Apolipoprotein E C9orf72 Protein - genetics Dementia Dementia disorders Female Frontotemporal dementia Frontotemporal Dementia - genetics Frontotemporal Dementia - pathology Genetic Association Studies Genetic Predisposition to Disease Humans Male Middle Aged Motor neuron diseases Whole Exome Sequencing |
| title | Genetics of dementia in a Finnish cohort |
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