Use of a genetic isolate to identify rare disease variants: C7 on 5p associated with MS

Suvi P Kallio, Eveliina Jakkula, Shaun Purcell, Minna Suvela, Keijo Koivisto, Pentti J Tienari, Irina Elovaara, Tuula Pirttilä, Mauri Reunanen, Denis Bronnikov, Markku Viander, Seppo Meri, Jan Hillert, Frida Lundmark, Hanne F Harbo, Åslaug R Lorenzen, Philip L De Jager, Mark J Daly, David A Hafler, Aarno PalotieLeena Peltonen, Janna Saarela

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Kuvaus

Large case-control genome-wide association studies primarily expose common variants contributing to disease pathogenesis with modest effects. Thus, alternative strategies are needed to tackle rare, possibly more penetrant alleles. One strategy is to use special populations with a founder effect and isolation, resulting in allelic enrichment. For multiple sclerosis such a unique setting is reported in Southern Ostrobothnia in Finland, where the prevalence and familial occurrence of multiple sclerosis (MS) are exceptionally high. Here, we have studied one of the best replicated MS loci, 5p, and monitored for haplotypes shared among 72 regional MS cases, the majority of which are genealogically distantly related. The haplotype analysis over the 45 Mb region, covering the linkage peak identified in Finnish MS families, revealed only modest association at IL7R (P = 0.04), recently implicated in MS, whereas most significant association was found with one haplotype covering the C7-FLJ40243 locus (P = 0.0001), 5.1 Mb centromeric of IL7R. The finding was validated in an independent sample from the isolate and resulted in an odds ratio of 2.73 (P = 0.000003) in the combined data set. The identified relatively rare risk haplotype contains C7 (complement component 7), an important player of the innate immune system. Suggestive association with alleles of the region was seen also in more heterogeneous populations. Interestingly, also the complement activity correlated with the identified risk haplotype. These results suggest that the MS predisposing locus on 5p is more complex than assumed and exemplify power of population isolates in the identification of rare disease alleles.
Alkuperäiskielienglanti
LehtiHuman Molecular Genetics
Vuosikerta18
Numero9
Sivut1670-1683
Sivumäärä14
ISSN0964-6906
DOI - pysyväislinkit
TilaJulkaistu - huhtikuuta 2009
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

  • 311 Peruslääketieteet
  • 312 Kliiniset lääketieteet
  • 318 Lääketieteen bioteknologia
  • 217 Lääketieteen tekniikka
  • 118 Biotieteet

Lainaa tätä

Kallio, Suvi P ; Jakkula, Eveliina ; Purcell, Shaun ; Suvela, Minna ; Koivisto, Keijo ; Tienari, Pentti J ; Elovaara, Irina ; Pirttilä, Tuula ; Reunanen, Mauri ; Bronnikov, Denis ; Viander, Markku ; Meri, Seppo ; Hillert, Jan ; Lundmark, Frida ; Harbo, Hanne F ; Lorenzen, Åslaug R ; De Jager, Philip L ; Daly, Mark J ; Hafler, David A ; Palotie, Aarno ; Peltonen, Leena ; Saarela, Janna. / Use of a genetic isolate to identify rare disease variants : C7 on 5p associated with MS. Julkaisussa: Human Molecular Genetics. 2009 ; Vuosikerta 18, Nro 9. Sivut 1670-1683.
@article{b399b85d7eb246fca5b93cad94daa297,
title = "Use of a genetic isolate to identify rare disease variants: C7 on 5p associated with MS",
abstract = "Large case-control genome-wide association studies primarily expose common variants contributing to disease pathogenesis with modest effects. Thus, alternative strategies are needed to tackle rare, possibly more penetrant alleles. One strategy is to use special populations with a founder effect and isolation, resulting in allelic enrichment. For multiple sclerosis such a unique setting is reported in Southern Ostrobothnia in Finland, where the prevalence and familial occurrence of multiple sclerosis (MS) are exceptionally high. Here, we have studied one of the best replicated MS loci, 5p, and monitored for haplotypes shared among 72 regional MS cases, the majority of which are genealogically distantly related. The haplotype analysis over the 45 Mb region, covering the linkage peak identified in Finnish MS families, revealed only modest association at IL7R (P = 0.04), recently implicated in MS, whereas most significant association was found with one haplotype covering the C7-FLJ40243 locus (P = 0.0001), 5.1 Mb centromeric of IL7R. The finding was validated in an independent sample from the isolate and resulted in an odds ratio of 2.73 (P = 0.000003) in the combined data set. The identified relatively rare risk haplotype contains C7 (complement component 7), an important player of the innate immune system. Suggestive association with alleles of the region was seen also in more heterogeneous populations. Interestingly, also the complement activity correlated with the identified risk haplotype. These results suggest that the MS predisposing locus on 5p is more complex than assumed and exemplify power of population isolates in the identification of rare disease alleles.",
keywords = "311 Basic medicine, 312 Clinical medicine, 318 Medical biotechnology, 217 Medical engineering, 118 Biological sciences",
author = "Kallio, {Suvi P} and Eveliina Jakkula and Shaun Purcell and Minna Suvela and Keijo Koivisto and Tienari, {Pentti J} and Irina Elovaara and Tuula Pirttil{\"a} and Mauri Reunanen and Denis Bronnikov and Markku Viander and Seppo Meri and Jan Hillert and Frida Lundmark and Harbo, {Hanne F} and Lorenzen, {{\AA}slaug R} and {De Jager}, {Philip L} and Daly, {Mark J} and Hafler, {David A} and Aarno Palotie and Leena Peltonen and Janna Saarela",
year = "2009",
month = "4",
doi = "10.1093/hmg/ddp073",
language = "English",
volume = "18",
pages = "1670--1683",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "9",

}

Kallio, SP, Jakkula, E, Purcell, S, Suvela, M, Koivisto, K, Tienari, PJ, Elovaara, I, Pirttilä, T, Reunanen, M, Bronnikov, D, Viander, M, Meri, S, Hillert, J, Lundmark, F, Harbo, HF, Lorenzen, ÅR, De Jager, PL, Daly, MJ, Hafler, DA, Palotie, A, Peltonen, L & Saarela, J 2009, 'Use of a genetic isolate to identify rare disease variants: C7 on 5p associated with MS', Human Molecular Genetics, Vuosikerta 18, Nro 9, Sivut 1670-1683. https://doi.org/10.1093/hmg/ddp073

Use of a genetic isolate to identify rare disease variants : C7 on 5p associated with MS. / Kallio, Suvi P; Jakkula, Eveliina; Purcell, Shaun; Suvela, Minna; Koivisto, Keijo; Tienari, Pentti J; Elovaara, Irina; Pirttilä, Tuula; Reunanen, Mauri; Bronnikov, Denis; Viander, Markku; Meri, Seppo; Hillert, Jan; Lundmark, Frida; Harbo, Hanne F; Lorenzen, Åslaug R; De Jager, Philip L; Daly, Mark J; Hafler, David A; Palotie, Aarno; Peltonen, Leena; Saarela, Janna.

julkaisussa: Human Molecular Genetics, Vuosikerta 18, Nro 9, 04.2009, s. 1670-1683.

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

TY - JOUR

T1 - Use of a genetic isolate to identify rare disease variants

T2 - C7 on 5p associated with MS

AU - Kallio, Suvi P

AU - Jakkula, Eveliina

AU - Purcell, Shaun

AU - Suvela, Minna

AU - Koivisto, Keijo

AU - Tienari, Pentti J

AU - Elovaara, Irina

AU - Pirttilä, Tuula

AU - Reunanen, Mauri

AU - Bronnikov, Denis

AU - Viander, Markku

AU - Meri, Seppo

AU - Hillert, Jan

AU - Lundmark, Frida

AU - Harbo, Hanne F

AU - Lorenzen, Åslaug R

AU - De Jager, Philip L

AU - Daly, Mark J

AU - Hafler, David A

AU - Palotie, Aarno

AU - Peltonen, Leena

AU - Saarela, Janna

PY - 2009/4

Y1 - 2009/4

N2 - Large case-control genome-wide association studies primarily expose common variants contributing to disease pathogenesis with modest effects. Thus, alternative strategies are needed to tackle rare, possibly more penetrant alleles. One strategy is to use special populations with a founder effect and isolation, resulting in allelic enrichment. For multiple sclerosis such a unique setting is reported in Southern Ostrobothnia in Finland, where the prevalence and familial occurrence of multiple sclerosis (MS) are exceptionally high. Here, we have studied one of the best replicated MS loci, 5p, and monitored for haplotypes shared among 72 regional MS cases, the majority of which are genealogically distantly related. The haplotype analysis over the 45 Mb region, covering the linkage peak identified in Finnish MS families, revealed only modest association at IL7R (P = 0.04), recently implicated in MS, whereas most significant association was found with one haplotype covering the C7-FLJ40243 locus (P = 0.0001), 5.1 Mb centromeric of IL7R. The finding was validated in an independent sample from the isolate and resulted in an odds ratio of 2.73 (P = 0.000003) in the combined data set. The identified relatively rare risk haplotype contains C7 (complement component 7), an important player of the innate immune system. Suggestive association with alleles of the region was seen also in more heterogeneous populations. Interestingly, also the complement activity correlated with the identified risk haplotype. These results suggest that the MS predisposing locus on 5p is more complex than assumed and exemplify power of population isolates in the identification of rare disease alleles.

AB - Large case-control genome-wide association studies primarily expose common variants contributing to disease pathogenesis with modest effects. Thus, alternative strategies are needed to tackle rare, possibly more penetrant alleles. One strategy is to use special populations with a founder effect and isolation, resulting in allelic enrichment. For multiple sclerosis such a unique setting is reported in Southern Ostrobothnia in Finland, where the prevalence and familial occurrence of multiple sclerosis (MS) are exceptionally high. Here, we have studied one of the best replicated MS loci, 5p, and monitored for haplotypes shared among 72 regional MS cases, the majority of which are genealogically distantly related. The haplotype analysis over the 45 Mb region, covering the linkage peak identified in Finnish MS families, revealed only modest association at IL7R (P = 0.04), recently implicated in MS, whereas most significant association was found with one haplotype covering the C7-FLJ40243 locus (P = 0.0001), 5.1 Mb centromeric of IL7R. The finding was validated in an independent sample from the isolate and resulted in an odds ratio of 2.73 (P = 0.000003) in the combined data set. The identified relatively rare risk haplotype contains C7 (complement component 7), an important player of the innate immune system. Suggestive association with alleles of the region was seen also in more heterogeneous populations. Interestingly, also the complement activity correlated with the identified risk haplotype. These results suggest that the MS predisposing locus on 5p is more complex than assumed and exemplify power of population isolates in the identification of rare disease alleles.

KW - 311 Basic medicine

KW - 312 Clinical medicine

KW - 318 Medical biotechnology

KW - 217 Medical engineering

KW - 118 Biological sciences

U2 - 10.1093/hmg/ddp073

DO - 10.1093/hmg/ddp073

M3 - Article

VL - 18

SP - 1670

EP - 1683

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 9

ER -