Consistently replicating locus linked to migraine on 10q22-q23

Verneri Anttila, Dale R Nyholt, Mikko Kallela, Ville Artto, Salli Vepsäläinen, Eveliina Jakkula, Annika Wennerström, Päivi Tikka-Kleemola, Mari A Kaunisto, Eija Hämäläinen, Elisabeth Widen, Joseph Terwilliger, Kathleen Merikangas, Grant W Montgomery, Nicholas G Martin, Mark Daly, Jaakko Kaprio, Leena Peltonen, Markus Färkkilä, Maija Wessman & 1 others Aarno Palotie

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Here, we present the results of two genome-wide scans in two diverse populations in which a consistent use of recently introduced migraine-phenotyping methods detects and replicates a locus on 10q22-q23, with an additional independent replication. No genetic variants have been convincingly established in migraine, and although several loci have been reported, none of them has been consistently replicated. We employed the three known migraine-phenotyping methods (clinical end diagnosis, latent-class analysis, and trait-component analysis) with robust multiple testing correction in a large sample set of 1675 individuals from 210 migraine families from Finland and Australia. Genome-wide multipoint linkage analysis that used the Kong and Cox exponential model in Finns detected a locus on 10q22-q23 with highly significant evidence of linkage (LOD 7.68 at 103 cM in female-specific analysis). The Australian sample showed a LOD score of 3.50 at the same locus (100 cM), as did the independent Finnish replication study (LOD score 2.41, at 102 cM). In addition, four previously reported loci on 8q21, 14q21, 18q12, and Xp21 were also replicated. A shared-segment analysis of 10q22-q23 linked Finnish families identified a 1.6-9.5 cM segment, centered on 101 cM, which shows in-family homology in 95% of affected Finns. This region was further studied with 1323 SNPs. Although no significant association was observed, four regions warranting follow-up studies were identified. These results support the use of symptomology-based phenotyping in migraine and suggest that the 10q22-q23 locus probably contains one or more migraine susceptibility variants.
Original languageEnglish
JournalAmerican Journal of Human Genetics
Volume82
Issue number5
Pages (from-to)1051-1063
Number of pages13
ISSN0002-9297
DOIs
Publication statusPublished - 2008
MoE publication typeA1 Journal article-refereed

Fields of Science

  • FAMILIAL HEMIPLEGIC MIGRAINE
  • GENOME-WIDE ASSOCIATION
  • LINKAGE ANALYSIS
  • SUSCEPTIBILITY LOCUS
  • COMPLEX TRAITS
  • MACULAR DEGENERATION
  • MULTIPLE-SCLEROSIS
  • GENETIC DISSECTION
  • PROSTATE-CANCER
  • INFLUENCES RISK

Cite this

Anttila, Verneri ; Nyholt, Dale R ; Kallela, Mikko ; Artto, Ville ; Vepsäläinen, Salli ; Jakkula, Eveliina ; Wennerström, Annika ; Tikka-Kleemola, Päivi ; Kaunisto, Mari A ; Hämäläinen, Eija ; Widen, Elisabeth ; Terwilliger, Joseph ; Merikangas, Kathleen ; Montgomery, Grant W ; Martin, Nicholas G ; Daly, Mark ; Kaprio, Jaakko ; Peltonen, Leena ; Färkkilä, Markus ; Wessman, Maija ; Palotie, Aarno. / Consistently replicating locus linked to migraine on 10q22-q23. In: American Journal of Human Genetics. 2008 ; Vol. 82, No. 5. pp. 1051-1063.
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abstract = "Here, we present the results of two genome-wide scans in two diverse populations in which a consistent use of recently introduced migraine-phenotyping methods detects and replicates a locus on 10q22-q23, with an additional independent replication. No genetic variants have been convincingly established in migraine, and although several loci have been reported, none of them has been consistently replicated. We employed the three known migraine-phenotyping methods (clinical end diagnosis, latent-class analysis, and trait-component analysis) with robust multiple testing correction in a large sample set of 1675 individuals from 210 migraine families from Finland and Australia. Genome-wide multipoint linkage analysis that used the Kong and Cox exponential model in Finns detected a locus on 10q22-q23 with highly significant evidence of linkage (LOD 7.68 at 103 cM in female-specific analysis). The Australian sample showed a LOD score of 3.50 at the same locus (100 cM), as did the independent Finnish replication study (LOD score 2.41, at 102 cM). In addition, four previously reported loci on 8q21, 14q21, 18q12, and Xp21 were also replicated. A shared-segment analysis of 10q22-q23 linked Finnish families identified a 1.6-9.5 cM segment, centered on 101 cM, which shows in-family homology in 95{\%} of affected Finns. This region was further studied with 1323 SNPs. Although no significant association was observed, four regions warranting follow-up studies were identified. These results support the use of symptomology-based phenotyping in migraine and suggest that the 10q22-q23 locus probably contains one or more migraine susceptibility variants.",
keywords = "FAMILIAL HEMIPLEGIC MIGRAINE, GENOME-WIDE ASSOCIATION, LINKAGE ANALYSIS, SUSCEPTIBILITY LOCUS, COMPLEX TRAITS, MACULAR DEGENERATION, MULTIPLE-SCLEROSIS, GENETIC DISSECTION, PROSTATE-CANCER, INFLUENCES RISK",
author = "Verneri Anttila and Nyholt, {Dale R} and Mikko Kallela and Ville Artto and Salli Veps{\"a}l{\"a}inen and Eveliina Jakkula and Annika Wennerstr{\"o}m and P{\"a}ivi Tikka-Kleemola and Kaunisto, {Mari A} and Eija H{\"a}m{\"a}l{\"a}inen and Elisabeth Widen and Joseph Terwilliger and Kathleen Merikangas and Montgomery, {Grant W} and Martin, {Nicholas G} and Mark Daly and Jaakko Kaprio and Leena Peltonen and Markus F{\"a}rkkil{\"a} and Maija Wessman and Aarno Palotie",
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language = "English",
volume = "82",
pages = "1051--1063",
journal = "American Journal of Human Genetics",
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Consistently replicating locus linked to migraine on 10q22-q23. / Anttila, Verneri; Nyholt, Dale R; Kallela, Mikko; Artto, Ville; Vepsäläinen, Salli; Jakkula, Eveliina; Wennerström, Annika; Tikka-Kleemola, Päivi; Kaunisto, Mari A; Hämäläinen, Eija; Widen, Elisabeth; Terwilliger, Joseph; Merikangas, Kathleen; Montgomery, Grant W; Martin, Nicholas G; Daly, Mark; Kaprio, Jaakko; Peltonen, Leena; Färkkilä, Markus; Wessman, Maija; Palotie, Aarno.

In: American Journal of Human Genetics, Vol. 82, No. 5, 2008, p. 1051-1063.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Consistently replicating locus linked to migraine on 10q22-q23

AU - Anttila, Verneri

AU - Nyholt, Dale R

AU - Kallela, Mikko

AU - Artto, Ville

AU - Vepsäläinen, Salli

AU - Jakkula, Eveliina

AU - Wennerström, Annika

AU - Tikka-Kleemola, Päivi

AU - Kaunisto, Mari A

AU - Hämäläinen, Eija

AU - Widen, Elisabeth

AU - Terwilliger, Joseph

AU - Merikangas, Kathleen

AU - Montgomery, Grant W

AU - Martin, Nicholas G

AU - Daly, Mark

AU - Kaprio, Jaakko

AU - Peltonen, Leena

AU - Färkkilä, Markus

AU - Wessman, Maija

AU - Palotie, Aarno

PY - 2008

Y1 - 2008

N2 - Here, we present the results of two genome-wide scans in two diverse populations in which a consistent use of recently introduced migraine-phenotyping methods detects and replicates a locus on 10q22-q23, with an additional independent replication. No genetic variants have been convincingly established in migraine, and although several loci have been reported, none of them has been consistently replicated. We employed the three known migraine-phenotyping methods (clinical end diagnosis, latent-class analysis, and trait-component analysis) with robust multiple testing correction in a large sample set of 1675 individuals from 210 migraine families from Finland and Australia. Genome-wide multipoint linkage analysis that used the Kong and Cox exponential model in Finns detected a locus on 10q22-q23 with highly significant evidence of linkage (LOD 7.68 at 103 cM in female-specific analysis). The Australian sample showed a LOD score of 3.50 at the same locus (100 cM), as did the independent Finnish replication study (LOD score 2.41, at 102 cM). In addition, four previously reported loci on 8q21, 14q21, 18q12, and Xp21 were also replicated. A shared-segment analysis of 10q22-q23 linked Finnish families identified a 1.6-9.5 cM segment, centered on 101 cM, which shows in-family homology in 95% of affected Finns. This region was further studied with 1323 SNPs. Although no significant association was observed, four regions warranting follow-up studies were identified. These results support the use of symptomology-based phenotyping in migraine and suggest that the 10q22-q23 locus probably contains one or more migraine susceptibility variants.

AB - Here, we present the results of two genome-wide scans in two diverse populations in which a consistent use of recently introduced migraine-phenotyping methods detects and replicates a locus on 10q22-q23, with an additional independent replication. No genetic variants have been convincingly established in migraine, and although several loci have been reported, none of them has been consistently replicated. We employed the three known migraine-phenotyping methods (clinical end diagnosis, latent-class analysis, and trait-component analysis) with robust multiple testing correction in a large sample set of 1675 individuals from 210 migraine families from Finland and Australia. Genome-wide multipoint linkage analysis that used the Kong and Cox exponential model in Finns detected a locus on 10q22-q23 with highly significant evidence of linkage (LOD 7.68 at 103 cM in female-specific analysis). The Australian sample showed a LOD score of 3.50 at the same locus (100 cM), as did the independent Finnish replication study (LOD score 2.41, at 102 cM). In addition, four previously reported loci on 8q21, 14q21, 18q12, and Xp21 were also replicated. A shared-segment analysis of 10q22-q23 linked Finnish families identified a 1.6-9.5 cM segment, centered on 101 cM, which shows in-family homology in 95% of affected Finns. This region was further studied with 1323 SNPs. Although no significant association was observed, four regions warranting follow-up studies were identified. These results support the use of symptomology-based phenotyping in migraine and suggest that the 10q22-q23 locus probably contains one or more migraine susceptibility variants.

KW - FAMILIAL HEMIPLEGIC MIGRAINE

KW - GENOME-WIDE ASSOCIATION

KW - LINKAGE ANALYSIS

KW - SUSCEPTIBILITY LOCUS

KW - COMPLEX TRAITS

KW - MACULAR DEGENERATION

KW - MULTIPLE-SCLEROSIS

KW - GENETIC DISSECTION

KW - PROSTATE-CANCER

KW - INFLUENCES RISK

U2 - 10.1016/j.ajhg.2008.03.003

DO - 10.1016/j.ajhg.2008.03.003

M3 - Article

VL - 82

SP - 1051

EP - 1063

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 5

ER -