C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity

C9orf72 hexanucleotide repeat expansion is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 locus may harbor residual risk outside the hexanucleotide repeat expansion, but the evidence is conflicting. Here, we first compared 683 unrelated amyotrophic lateral sclerosis cases and 3,196 controls with Finnish ancestry to find best single nucleotide polymorphisms that tag the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles. Rs2814707 was the best tagging single nucleotide polymorphisms for intermediate-length alleles with ≥7 repeats (p = 5 × 10−307) and rs139185008 for the hexanucleotide repeat expansion (p = 7 × 10−114) as well as alleles with ≥20 repeats. rs139185008*C associated with amyotrophic lateral sclerosis after removing cases with the hexanucleotide repeat expansion, especially in the subpopulation homozygous for the rs2814707*T (p = 0.0002, OR = 5.06), which supports the concept of residual amyotrophic lateral sclerosis risk at the C9orf72 haplotypes other than the hexanucleotide repeat expansion. We then leveraged Finnish biobank data to test the effects of rs2814707*T and rs139185008*C on longevity after removing individuals with amyotrophic lateral sclerosis / frontotemporal dementia diagnoses. In the discovery cohort (n = 230,006), the frequency of rs139185008*C heterozygotes decreased significantly with age in the comparisons between 50 and 80 years vs. >80 years (p = 0.0005) and <50 years vs. >80 years (p = 0.0001). The findings were similar but less significant in a smaller replication cohort (2-sided p = 0.037 in 50–80 years vs. >80 years and 0.061 in <50 years vs. >80 years). Analysis of the allele frequencies in 5-year bins demonstrated that the decrease of rs139185008*C started after the age of 70 years. The hexanucleotide repeat expansion tagging single nucleotide polymorphisms decreasing frequency with age suggests its’ association with age-related diseases probably also outside amyotrophic lateral sclerosis / frontotemporal dementia. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Karri Kaivola [verfasserIn] Matti Pirinen [verfasserIn] Hannu Laaksovirta [verfasserIn] Lilja Jansson [verfasserIn] Osma Rautila [verfasserIn] Jyrki Launes [verfasserIn] Laura Hokkanen [verfasserIn] Jari Lahti [verfasserIn] Johan G. Eriksson [verfasserIn] Timo E. Strandberg [verfasserIn] FinnGen [verfasserIn] Pentti J. Tienari [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	C9orf72 ALS intermediate allele survival case-control analysis biobank

Übergeordnetes Werk:	In: Frontiers in Genetics - Frontiers Media S.A., 2011, 14(2023)
Übergeordnetes Werk:	volume:14 ; year:2023

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fgene.2023.1087098

Katalog-ID:	DOAJ088385809

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allfields	10.3389/fgene.2023.1087098 doi (DE-627)DOAJ088385809 (DE-599)DOAJ2e5229c504f94b7f82b772d45f2f0651 DE-627 ger DE-627 rakwb eng QH426-470 Karri Kaivola verfasserin aut C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier C9orf72 hexanucleotide repeat expansion is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 locus may harbor residual risk outside the hexanucleotide repeat expansion, but the evidence is conflicting. Here, we first compared 683 unrelated amyotrophic lateral sclerosis cases and 3,196 controls with Finnish ancestry to find best single nucleotide polymorphisms that tag the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles. Rs2814707 was the best tagging single nucleotide polymorphisms for intermediate-length alleles with ≥7 repeats (p = 5 × 10−307) and rs139185008 for the hexanucleotide repeat expansion (p = 7 × 10−114) as well as alleles with ≥20 repeats. rs139185008C associated with amyotrophic lateral sclerosis after removing cases with the hexanucleotide repeat expansion, especially in the subpopulation homozygous for the rs2814707T (p = 0.0002, OR = 5.06), which supports the concept of residual amyotrophic lateral sclerosis risk at the C9orf72 haplotypes other than the hexanucleotide repeat expansion. We then leveraged Finnish biobank data to test the effects of rs2814707T and rs139185008C on longevity after removing individuals with amyotrophic lateral sclerosis / frontotemporal dementia diagnoses. In the discovery cohort (n = 230,006), the frequency of rs139185008C heterozygotes decreased significantly with age in the comparisons between 50 and 80 years vs. >80 years (p = 0.0005) and <50 years vs. >80 years (p = 0.0001). The findings were similar but less significant in a smaller replication cohort (2-sided p = 0.037 in 50–80 years vs. >80 years and 0.061 in <50 years vs. >80 years). Analysis of the allele frequencies in 5-year bins demonstrated that the decrease of rs139185008C started after the age of 70 years. The hexanucleotide repeat expansion tagging single nucleotide polymorphisms decreasing frequency with age suggests its’ association with age-related diseases probably also outside amyotrophic lateral sclerosis / frontotemporal dementia. C9orf72 ALS intermediate allele survival case-control analysis biobank Genetics Karri Kaivola verfasserin aut Matti Pirinen verfasserin aut Matti Pirinen verfasserin aut Matti Pirinen verfasserin aut Hannu Laaksovirta verfasserin aut Lilja Jansson verfasserin aut Lilja Jansson verfasserin aut Osma Rautila verfasserin aut Osma Rautila verfasserin aut Jyrki Launes verfasserin aut Laura Hokkanen verfasserin aut Jari Lahti verfasserin aut Johan G. Eriksson verfasserin aut Johan G. Eriksson verfasserin aut Johan G. Eriksson verfasserin aut Johan G. Eriksson verfasserin aut Timo E. Strandberg verfasserin aut Timo E. Strandberg verfasserin aut FinnGen verfasserin aut Pentti J. Tienari verfasserin aut Pentti J. Tienari verfasserin aut In Frontiers in Genetics Frontiers Media S.A., 2011 14(2023) (DE-627)65799829X (DE-600)2606823-0 16648021 nnns volume:14 year:2023 https://doi.org/10.3389/fgene.2023.1087098 kostenfrei https://doaj.org/article/2e5229c504f94b7f82b772d45f2f0651 kostenfrei https://www.frontiersin.org/articles/10.3389/fgene.2023.1087098/full kostenfrei https://doaj.org/toc/1664-8021 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023
spelling	10.3389/fgene.2023.1087098 doi (DE-627)DOAJ088385809 (DE-599)DOAJ2e5229c504f94b7f82b772d45f2f0651 DE-627 ger DE-627 rakwb eng QH426-470 Karri Kaivola verfasserin aut C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier C9orf72 hexanucleotide repeat expansion is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 locus may harbor residual risk outside the hexanucleotide repeat expansion, but the evidence is conflicting. Here, we first compared 683 unrelated amyotrophic lateral sclerosis cases and 3,196 controls with Finnish ancestry to find best single nucleotide polymorphisms that tag the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles. Rs2814707 was the best tagging single nucleotide polymorphisms for intermediate-length alleles with ≥7 repeats (p = 5 × 10−307) and rs139185008 for the hexanucleotide repeat expansion (p = 7 × 10−114) as well as alleles with ≥20 repeats. rs139185008C associated with amyotrophic lateral sclerosis after removing cases with the hexanucleotide repeat expansion, especially in the subpopulation homozygous for the rs2814707T (p = 0.0002, OR = 5.06), which supports the concept of residual amyotrophic lateral sclerosis risk at the C9orf72 haplotypes other than the hexanucleotide repeat expansion. We then leveraged Finnish biobank data to test the effects of rs2814707T and rs139185008C on longevity after removing individuals with amyotrophic lateral sclerosis / frontotemporal dementia diagnoses. In the discovery cohort (n = 230,006), the frequency of rs139185008C heterozygotes decreased significantly with age in the comparisons between 50 and 80 years vs. >80 years (p = 0.0005) and <50 years vs. >80 years (p = 0.0001). The findings were similar but less significant in a smaller replication cohort (2-sided p = 0.037 in 50–80 years vs. >80 years and 0.061 in <50 years vs. >80 years). Analysis of the allele frequencies in 5-year bins demonstrated that the decrease of rs139185008C started after the age of 70 years. The hexanucleotide repeat expansion tagging single nucleotide polymorphisms decreasing frequency with age suggests its’ association with age-related diseases probably also outside amyotrophic lateral sclerosis / frontotemporal dementia. C9orf72 ALS intermediate allele survival case-control analysis biobank Genetics Karri Kaivola verfasserin aut Matti Pirinen verfasserin aut Matti Pirinen verfasserin aut Matti Pirinen verfasserin aut Hannu Laaksovirta verfasserin aut Lilja Jansson verfasserin aut Lilja Jansson verfasserin aut Osma Rautila verfasserin aut Osma Rautila verfasserin aut Jyrki Launes verfasserin aut Laura Hokkanen verfasserin aut Jari Lahti verfasserin aut Johan G. Eriksson verfasserin aut Johan G. Eriksson verfasserin aut Johan G. Eriksson verfasserin aut Johan G. Eriksson verfasserin aut Timo E. Strandberg verfasserin aut Timo E. Strandberg verfasserin aut FinnGen verfasserin aut Pentti J. Tienari verfasserin aut Pentti J. Tienari verfasserin aut In Frontiers in Genetics Frontiers Media S.A., 2011 14(2023) (DE-627)65799829X (DE-600)2606823-0 16648021 nnns volume:14 year:2023 https://doi.org/10.3389/fgene.2023.1087098 kostenfrei https://doaj.org/article/2e5229c504f94b7f82b772d45f2f0651 kostenfrei https://www.frontiersin.org/articles/10.3389/fgene.2023.1087098/full kostenfrei https://doaj.org/toc/1664-8021 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023
allfields_unstemmed	10.3389/fgene.2023.1087098 doi (DE-627)DOAJ088385809 (DE-599)DOAJ2e5229c504f94b7f82b772d45f2f0651 DE-627 ger DE-627 rakwb eng QH426-470 Karri Kaivola verfasserin aut C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier C9orf72 hexanucleotide repeat expansion is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 locus may harbor residual risk outside the hexanucleotide repeat expansion, but the evidence is conflicting. Here, we first compared 683 unrelated amyotrophic lateral sclerosis cases and 3,196 controls with Finnish ancestry to find best single nucleotide polymorphisms that tag the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles. Rs2814707 was the best tagging single nucleotide polymorphisms for intermediate-length alleles with ≥7 repeats (p = 5 × 10−307) and rs139185008 for the hexanucleotide repeat expansion (p = 7 × 10−114) as well as alleles with ≥20 repeats. rs139185008C associated with amyotrophic lateral sclerosis after removing cases with the hexanucleotide repeat expansion, especially in the subpopulation homozygous for the rs2814707T (p = 0.0002, OR = 5.06), which supports the concept of residual amyotrophic lateral sclerosis risk at the C9orf72 haplotypes other than the hexanucleotide repeat expansion. We then leveraged Finnish biobank data to test the effects of rs2814707T and rs139185008C on longevity after removing individuals with amyotrophic lateral sclerosis / frontotemporal dementia diagnoses. In the discovery cohort (n = 230,006), the frequency of rs139185008C heterozygotes decreased significantly with age in the comparisons between 50 and 80 years vs. >80 years (p = 0.0005) and <50 years vs. >80 years (p = 0.0001). The findings were similar but less significant in a smaller replication cohort (2-sided p = 0.037 in 50–80 years vs. >80 years and 0.061 in <50 years vs. >80 years). Analysis of the allele frequencies in 5-year bins demonstrated that the decrease of rs139185008C started after the age of 70 years. The hexanucleotide repeat expansion tagging single nucleotide polymorphisms decreasing frequency with age suggests its’ association with age-related diseases probably also outside amyotrophic lateral sclerosis / frontotemporal dementia. C9orf72 ALS intermediate allele survival case-control analysis biobank Genetics Karri Kaivola verfasserin aut Matti Pirinen verfasserin aut Matti Pirinen verfasserin aut Matti Pirinen verfasserin aut Hannu Laaksovirta verfasserin aut Lilja Jansson verfasserin aut Lilja Jansson verfasserin aut Osma Rautila verfasserin aut Osma Rautila verfasserin aut Jyrki Launes verfasserin aut Laura Hokkanen verfasserin aut Jari Lahti verfasserin aut Johan G. Eriksson verfasserin aut Johan G. Eriksson verfasserin aut Johan G. Eriksson verfasserin aut Johan G. Eriksson verfasserin aut Timo E. Strandberg verfasserin aut Timo E. Strandberg verfasserin aut FinnGen verfasserin aut Pentti J. Tienari verfasserin aut Pentti J. Tienari verfasserin aut In Frontiers in Genetics Frontiers Media S.A., 2011 14(2023) (DE-627)65799829X (DE-600)2606823-0 16648021 nnns volume:14 year:2023 https://doi.org/10.3389/fgene.2023.1087098 kostenfrei https://doaj.org/article/2e5229c504f94b7f82b772d45f2f0651 kostenfrei https://www.frontiersin.org/articles/10.3389/fgene.2023.1087098/full kostenfrei https://doaj.org/toc/1664-8021 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023
allfieldsGer	10.3389/fgene.2023.1087098 doi (DE-627)DOAJ088385809 (DE-599)DOAJ2e5229c504f94b7f82b772d45f2f0651 DE-627 ger DE-627 rakwb eng QH426-470 Karri Kaivola verfasserin aut C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier C9orf72 hexanucleotide repeat expansion is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 locus may harbor residual risk outside the hexanucleotide repeat expansion, but the evidence is conflicting. Here, we first compared 683 unrelated amyotrophic lateral sclerosis cases and 3,196 controls with Finnish ancestry to find best single nucleotide polymorphisms that tag the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles. Rs2814707 was the best tagging single nucleotide polymorphisms for intermediate-length alleles with ≥7 repeats (p = 5 × 10−307) and rs139185008 for the hexanucleotide repeat expansion (p = 7 × 10−114) as well as alleles with ≥20 repeats. rs139185008C associated with amyotrophic lateral sclerosis after removing cases with the hexanucleotide repeat expansion, especially in the subpopulation homozygous for the rs2814707T (p = 0.0002, OR = 5.06), which supports the concept of residual amyotrophic lateral sclerosis risk at the C9orf72 haplotypes other than the hexanucleotide repeat expansion. We then leveraged Finnish biobank data to test the effects of rs2814707T and rs139185008C on longevity after removing individuals with amyotrophic lateral sclerosis / frontotemporal dementia diagnoses. In the discovery cohort (n = 230,006), the frequency of rs139185008C heterozygotes decreased significantly with age in the comparisons between 50 and 80 years vs. >80 years (p = 0.0005) and <50 years vs. >80 years (p = 0.0001). The findings were similar but less significant in a smaller replication cohort (2-sided p = 0.037 in 50–80 years vs. >80 years and 0.061 in <50 years vs. >80 years). Analysis of the allele frequencies in 5-year bins demonstrated that the decrease of rs139185008C started after the age of 70 years. The hexanucleotide repeat expansion tagging single nucleotide polymorphisms decreasing frequency with age suggests its’ association with age-related diseases probably also outside amyotrophic lateral sclerosis / frontotemporal dementia. C9orf72 ALS intermediate allele survival case-control analysis biobank Genetics Karri Kaivola verfasserin aut Matti Pirinen verfasserin aut Matti Pirinen verfasserin aut Matti Pirinen verfasserin aut Hannu Laaksovirta verfasserin aut Lilja Jansson verfasserin aut Lilja Jansson verfasserin aut Osma Rautila verfasserin aut Osma Rautila verfasserin aut Jyrki Launes verfasserin aut Laura Hokkanen verfasserin aut Jari Lahti verfasserin aut Johan G. Eriksson verfasserin aut Johan G. Eriksson verfasserin aut Johan G. Eriksson verfasserin aut Johan G. Eriksson verfasserin aut Timo E. Strandberg verfasserin aut Timo E. Strandberg verfasserin aut FinnGen verfasserin aut Pentti J. Tienari verfasserin aut Pentti J. Tienari verfasserin aut In Frontiers in Genetics Frontiers Media S.A., 2011 14(2023) (DE-627)65799829X (DE-600)2606823-0 16648021 nnns volume:14 year:2023 https://doi.org/10.3389/fgene.2023.1087098 kostenfrei https://doaj.org/article/2e5229c504f94b7f82b772d45f2f0651 kostenfrei https://www.frontiersin.org/articles/10.3389/fgene.2023.1087098/full kostenfrei https://doaj.org/toc/1664-8021 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023
allfieldsSound	10.3389/fgene.2023.1087098 doi (DE-627)DOAJ088385809 (DE-599)DOAJ2e5229c504f94b7f82b772d45f2f0651 DE-627 ger DE-627 rakwb eng QH426-470 Karri Kaivola verfasserin aut C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier C9orf72 hexanucleotide repeat expansion is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 locus may harbor residual risk outside the hexanucleotide repeat expansion, but the evidence is conflicting. Here, we first compared 683 unrelated amyotrophic lateral sclerosis cases and 3,196 controls with Finnish ancestry to find best single nucleotide polymorphisms that tag the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles. Rs2814707 was the best tagging single nucleotide polymorphisms for intermediate-length alleles with ≥7 repeats (p = 5 × 10−307) and rs139185008 for the hexanucleotide repeat expansion (p = 7 × 10−114) as well as alleles with ≥20 repeats. rs139185008C associated with amyotrophic lateral sclerosis after removing cases with the hexanucleotide repeat expansion, especially in the subpopulation homozygous for the rs2814707T (p = 0.0002, OR = 5.06), which supports the concept of residual amyotrophic lateral sclerosis risk at the C9orf72 haplotypes other than the hexanucleotide repeat expansion. We then leveraged Finnish biobank data to test the effects of rs2814707T and rs139185008C on longevity after removing individuals with amyotrophic lateral sclerosis / frontotemporal dementia diagnoses. In the discovery cohort (n = 230,006), the frequency of rs139185008C heterozygotes decreased significantly with age in the comparisons between 50 and 80 years vs. >80 years (p = 0.0005) and <50 years vs. >80 years (p = 0.0001). The findings were similar but less significant in a smaller replication cohort (2-sided p = 0.037 in 50–80 years vs. >80 years and 0.061 in <50 years vs. >80 years). Analysis of the allele frequencies in 5-year bins demonstrated that the decrease of rs139185008C started after the age of 70 years. The hexanucleotide repeat expansion tagging single nucleotide polymorphisms decreasing frequency with age suggests its’ association with age-related diseases probably also outside amyotrophic lateral sclerosis / frontotemporal dementia. C9orf72 ALS intermediate allele survival case-control analysis biobank Genetics Karri Kaivola verfasserin aut Matti Pirinen verfasserin aut Matti Pirinen verfasserin aut Matti Pirinen verfasserin aut Hannu Laaksovirta verfasserin aut Lilja Jansson verfasserin aut Lilja Jansson verfasserin aut Osma Rautila verfasserin aut Osma Rautila verfasserin aut Jyrki Launes verfasserin aut Laura Hokkanen verfasserin aut Jari Lahti verfasserin aut Johan G. Eriksson verfasserin aut Johan G. Eriksson verfasserin aut Johan G. Eriksson verfasserin aut Johan G. Eriksson verfasserin aut Timo E. Strandberg verfasserin aut Timo E. Strandberg verfasserin aut FinnGen verfasserin aut Pentti J. Tienari verfasserin aut Pentti J. Tienari verfasserin aut In Frontiers in Genetics Frontiers Media S.A., 2011 14(2023) (DE-627)65799829X (DE-600)2606823-0 16648021 nnns volume:14 year:2023 https://doi.org/10.3389/fgene.2023.1087098 kostenfrei https://doaj.org/article/2e5229c504f94b7f82b772d45f2f0651 kostenfrei https://www.frontiersin.org/articles/10.3389/fgene.2023.1087098/full kostenfrei https://doaj.org/toc/1664-8021 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023
language	English
source	In Frontiers in Genetics 14(2023) volume:14 year:2023
sourceStr	In Frontiers in Genetics 14(2023) volume:14 year:2023
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	C9orf72 ALS intermediate allele survival case-control analysis biobank Genetics
isfreeaccess_bool	true
container_title	Frontiers in Genetics
authorswithroles_txt_mv	Karri Kaivola @@aut@@ Matti Pirinen @@aut@@ Hannu Laaksovirta @@aut@@ Lilja Jansson @@aut@@ Osma Rautila @@aut@@ Jyrki Launes @@aut@@ Laura Hokkanen @@aut@@ Jari Lahti @@aut@@ Johan G. Eriksson @@aut@@ Timo E. Strandberg @@aut@@ FinnGen @@aut@@ Pentti J. Tienari @@aut@@
publishDateDaySort_date	2023-01-01T00:00:00Z
hierarchy_top_id	65799829X
id	DOAJ088385809
language_de	englisch
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callnumber-first	Q - Science
author	Karri Kaivola
spellingShingle	Karri Kaivola misc QH426-470 misc C9orf72 misc ALS misc intermediate allele misc survival misc case-control analysis misc biobank misc Genetics C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity
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topic_title	QH426-470 C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity C9orf72 ALS intermediate allele survival case-control analysis biobank
topic	misc QH426-470 misc C9orf72 misc ALS misc intermediate allele misc survival misc case-control analysis misc biobank misc Genetics
topic_unstemmed	misc QH426-470 misc C9orf72 misc ALS misc intermediate allele misc survival misc case-control analysis misc biobank misc Genetics
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title	C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity
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title_full	C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity
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author_browse	Karri Kaivola Matti Pirinen Hannu Laaksovirta Lilja Jansson Osma Rautila Jyrki Launes Laura Hokkanen Jari Lahti Johan G. Eriksson Timo E. Strandberg FinnGen Pentti J. Tienari
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title_sort	c9orf72 hexanucleotide repeat allele tagging snps: associations with als risk and longevity
callnumber	QH426-470
title_auth	C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity
abstract	C9orf72 hexanucleotide repeat expansion is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 locus may harbor residual risk outside the hexanucleotide repeat expansion, but the evidence is conflicting. Here, we first compared 683 unrelated amyotrophic lateral sclerosis cases and 3,196 controls with Finnish ancestry to find best single nucleotide polymorphisms that tag the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles. Rs2814707 was the best tagging single nucleotide polymorphisms for intermediate-length alleles with ≥7 repeats (p = 5 × 10−307) and rs139185008 for the hexanucleotide repeat expansion (p = 7 × 10−114) as well as alleles with ≥20 repeats. rs139185008C associated with amyotrophic lateral sclerosis after removing cases with the hexanucleotide repeat expansion, especially in the subpopulation homozygous for the rs2814707T (p = 0.0002, OR = 5.06), which supports the concept of residual amyotrophic lateral sclerosis risk at the C9orf72 haplotypes other than the hexanucleotide repeat expansion. We then leveraged Finnish biobank data to test the effects of rs2814707T and rs139185008C on longevity after removing individuals with amyotrophic lateral sclerosis / frontotemporal dementia diagnoses. In the discovery cohort (n = 230,006), the frequency of rs139185008C heterozygotes decreased significantly with age in the comparisons between 50 and 80 years vs. >80 years (p = 0.0005) and <50 years vs. >80 years (p = 0.0001). The findings were similar but less significant in a smaller replication cohort (2-sided p = 0.037 in 50–80 years vs. >80 years and 0.061 in <50 years vs. >80 years). Analysis of the allele frequencies in 5-year bins demonstrated that the decrease of rs139185008C started after the age of 70 years. The hexanucleotide repeat expansion tagging single nucleotide polymorphisms decreasing frequency with age suggests its’ association with age-related diseases probably also outside amyotrophic lateral sclerosis / frontotemporal dementia.
abstractGer	C9orf72 hexanucleotide repeat expansion is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 locus may harbor residual risk outside the hexanucleotide repeat expansion, but the evidence is conflicting. Here, we first compared 683 unrelated amyotrophic lateral sclerosis cases and 3,196 controls with Finnish ancestry to find best single nucleotide polymorphisms that tag the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles. Rs2814707 was the best tagging single nucleotide polymorphisms for intermediate-length alleles with ≥7 repeats (p = 5 × 10−307) and rs139185008 for the hexanucleotide repeat expansion (p = 7 × 10−114) as well as alleles with ≥20 repeats. rs139185008C associated with amyotrophic lateral sclerosis after removing cases with the hexanucleotide repeat expansion, especially in the subpopulation homozygous for the rs2814707T (p = 0.0002, OR = 5.06), which supports the concept of residual amyotrophic lateral sclerosis risk at the C9orf72 haplotypes other than the hexanucleotide repeat expansion. We then leveraged Finnish biobank data to test the effects of rs2814707T and rs139185008C on longevity after removing individuals with amyotrophic lateral sclerosis / frontotemporal dementia diagnoses. In the discovery cohort (n = 230,006), the frequency of rs139185008C heterozygotes decreased significantly with age in the comparisons between 50 and 80 years vs. >80 years (p = 0.0005) and <50 years vs. >80 years (p = 0.0001). The findings were similar but less significant in a smaller replication cohort (2-sided p = 0.037 in 50–80 years vs. >80 years and 0.061 in <50 years vs. >80 years). Analysis of the allele frequencies in 5-year bins demonstrated that the decrease of rs139185008C started after the age of 70 years. The hexanucleotide repeat expansion tagging single nucleotide polymorphisms decreasing frequency with age suggests its’ association with age-related diseases probably also outside amyotrophic lateral sclerosis / frontotemporal dementia.
abstract_unstemmed	C9orf72 hexanucleotide repeat expansion is a common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The C9orf72 locus may harbor residual risk outside the hexanucleotide repeat expansion, but the evidence is conflicting. Here, we first compared 683 unrelated amyotrophic lateral sclerosis cases and 3,196 controls with Finnish ancestry to find best single nucleotide polymorphisms that tag the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles. Rs2814707 was the best tagging single nucleotide polymorphisms for intermediate-length alleles with ≥7 repeats (p = 5 × 10−307) and rs139185008 for the hexanucleotide repeat expansion (p = 7 × 10−114) as well as alleles with ≥20 repeats. rs139185008C associated with amyotrophic lateral sclerosis after removing cases with the hexanucleotide repeat expansion, especially in the subpopulation homozygous for the rs2814707T (p = 0.0002, OR = 5.06), which supports the concept of residual amyotrophic lateral sclerosis risk at the C9orf72 haplotypes other than the hexanucleotide repeat expansion. We then leveraged Finnish biobank data to test the effects of rs2814707T and rs139185008C on longevity after removing individuals with amyotrophic lateral sclerosis / frontotemporal dementia diagnoses. In the discovery cohort (n = 230,006), the frequency of rs139185008C heterozygotes decreased significantly with age in the comparisons between 50 and 80 years vs. >80 years (p = 0.0005) and <50 years vs. >80 years (p = 0.0001). The findings were similar but less significant in a smaller replication cohort (2-sided p = 0.037 in 50–80 years vs. >80 years and 0.061 in <50 years vs. >80 years). Analysis of the allele frequencies in 5-year bins demonstrated that the decrease of rs139185008C started after the age of 70 years. The hexanucleotide repeat expansion tagging single nucleotide polymorphisms decreasing frequency with age suggests its’ association with age-related diseases probably also outside amyotrophic lateral sclerosis / frontotemporal dementia.
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title_short	C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity
url	https://doi.org/10.3389/fgene.2023.1087098 https://doaj.org/article/2e5229c504f94b7f82b772d45f2f0651 https://www.frontiersin.org/articles/10.3389/fgene.2023.1087098/full https://doaj.org/toc/1664-8021
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author2Str	Karri Kaivola Matti Pirinen Hannu Laaksovirta Lilja Jansson Osma Rautila Jyrki Launes Laura Hokkanen Jari Lahti Johan G. Eriksson Timo E. Strandberg FinnGen Pentti J. Tienari
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The C9orf72 locus may harbor residual risk outside the hexanucleotide repeat expansion, but the evidence is conflicting. Here, we first compared 683 unrelated amyotrophic lateral sclerosis cases and 3,196 controls with Finnish ancestry to find best single nucleotide polymorphisms that tag the C9orf72 hexanucleotide repeat expansion and intermediate-length alleles. Rs2814707 was the best tagging single nucleotide polymorphisms for intermediate-length alleles with ≥7 repeats (p = 5 × 10−307) and rs139185008 for the hexanucleotide repeat expansion (p = 7 × 10−114) as well as alleles with ≥20 repeats. rs139185008C associated with amyotrophic lateral sclerosis after removing cases with the hexanucleotide repeat expansion, especially in the subpopulation homozygous for the rs2814707T (p = 0.0002, OR = 5.06), which supports the concept of residual amyotrophic lateral sclerosis risk at the C9orf72 haplotypes other than the hexanucleotide repeat expansion. We then leveraged Finnish biobank data to test the effects of rs2814707T and rs139185008C on longevity after removing individuals with amyotrophic lateral sclerosis / frontotemporal dementia diagnoses. In the discovery cohort (n = 230,006), the frequency of rs139185008C heterozygotes decreased significantly with age in the comparisons between 50 and 80 years vs. &gt;80 years (p = 0.0005) and &lt;50 years vs. &gt;80 years (p = 0.0001). The findings were similar but less significant in a smaller replication cohort (2-sided p = 0.037 in 50–80 years vs. &gt;80 years and 0.061 in &lt;50 years vs. &gt;80 years). Analysis of the allele frequencies in 5-year bins demonstrated that the decrease of rs139185008C started after the age of 70 years. 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C9orf72 hexanucleotide repeat allele tagging SNPs: Associations with ALS risk and longevity

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