The first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder

Strong evidence of epistatic effects between loci on chromosomes 2q and 6q

Rami Abou Jamra, Robert Fuerst, Radka Kaneva, Guillermo Orozco Diaz, Fabio Rivas, Fermin Mayoral, Eudoxia Gay, Sebastian Sans, Maria Jose González, Susana Gil, Francisco Cabaleiro, Francisco Del Rio, Fermin Perez, Jesus Haro, Georg Auburger, Vihra Milanova, Christian Kostov, Vesselin Chorbov, Vessela Stoyanova, Amelia Nikolova-Hill & 10 others George Onchev, Ivo Kremensky, Assen Jablensky, Thomas G. Schulze, Peter Propping, Marcella Rietschel, Markus M. Nöthen, Sven Cichon, Thomas F. Wienker, Johannes Schumacher

Research output: Contribution to journalArticle

Abstract

We present the first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder (BPAD), using a large linkage data set (52 families of European descent; 448 participants and 259 affected individuals). Our results provide the strongest interaction evidence between BPAD genes on chromosomes 2q22-q24 and 6q23-q24, which was observed symmetrically in both directions (nonparametric LOD [NPL] scores of 7.55 on 2q and 7.63 on 6q; P <.0001 and , respectively, after a genomewide permutation procedure). The second-best BPAD interaction evidence P = .0001 was observed between chromosomes 2q22-q24 and 15q26. Here, we also observed a symmetrical interaction (NPL scores of 6.26 on 2q and 4.59 on 15q; and .0022, respectively). We covered the implicated regions by genotyping P = .0057 additional marker sets and performed a detailed interaction linkage analysis, which narrowed the susceptibility intervals. Although the heterogeneity analysis produced less impressive results (highest NPL score of 3.32) and a less consistent picture, we achieved evidence of locus heterogeneity at chromosomes 2q, 6p, 11p, 13q, and 22q, which was supported by adjacent markers within each region and by previously reported BPAD linkage findings. Our results provide systematic insights in the framework of BPAD epistasis and locus heterogeneity, which should facilitate gene identification by the use of more-comprehensive cloning strategies.

Original languageEnglish (US)
Pages (from-to)974-986
Number of pages13
JournalAmerican Journal of Human Genetics
Volume81
Issue number5
DOIs
StatePublished - 2007
Externally publishedYes

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Mood Disorders
Bipolar Disorder
Chromosomes
Genes
Organism Cloning

ASJC Scopus subject areas

  • Genetics

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The first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder : Strong evidence of epistatic effects between loci on chromosomes 2q and 6q. / Jamra, Rami Abou; Fuerst, Robert; Kaneva, Radka; Diaz, Guillermo Orozco; Rivas, Fabio; Mayoral, Fermin; Gay, Eudoxia; Sans, Sebastian; González, Maria Jose; Gil, Susana; Cabaleiro, Francisco; Del Rio, Francisco; Perez, Fermin; Haro, Jesus; Auburger, Georg; Milanova, Vihra; Kostov, Christian; Chorbov, Vesselin; Stoyanova, Vessela; Nikolova-Hill, Amelia; Onchev, George; Kremensky, Ivo; Jablensky, Assen; Schulze, Thomas G.; Propping, Peter; Rietschel, Marcella; Nöthen, Markus M.; Cichon, Sven; Wienker, Thomas F.; Schumacher, Johannes.

In: American Journal of Human Genetics, Vol. 81, No. 5, 2007, p. 974-986.

Research output: Contribution to journalArticle

Jamra, RA, Fuerst, R, Kaneva, R, Diaz, GO, Rivas, F, Mayoral, F, Gay, E, Sans, S, González, MJ, Gil, S, Cabaleiro, F, Del Rio, F, Perez, F, Haro, J, Auburger, G, Milanova, V, Kostov, C, Chorbov, V, Stoyanova, V, Nikolova-Hill, A, Onchev, G, Kremensky, I, Jablensky, A, Schulze, TG, Propping, P, Rietschel, M, Nöthen, MM, Cichon, S, Wienker, TF & Schumacher, J 2007, 'The first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder: Strong evidence of epistatic effects between loci on chromosomes 2q and 6q', American Journal of Human Genetics, vol. 81, no. 5, pp. 974-986. https://doi.org/10.1086/521690
Jamra, Rami Abou ; Fuerst, Robert ; Kaneva, Radka ; Diaz, Guillermo Orozco ; Rivas, Fabio ; Mayoral, Fermin ; Gay, Eudoxia ; Sans, Sebastian ; González, Maria Jose ; Gil, Susana ; Cabaleiro, Francisco ; Del Rio, Francisco ; Perez, Fermin ; Haro, Jesus ; Auburger, Georg ; Milanova, Vihra ; Kostov, Christian ; Chorbov, Vesselin ; Stoyanova, Vessela ; Nikolova-Hill, Amelia ; Onchev, George ; Kremensky, Ivo ; Jablensky, Assen ; Schulze, Thomas G. ; Propping, Peter ; Rietschel, Marcella ; Nöthen, Markus M. ; Cichon, Sven ; Wienker, Thomas F. ; Schumacher, Johannes. / The first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder : Strong evidence of epistatic effects between loci on chromosomes 2q and 6q. In: American Journal of Human Genetics. 2007 ; Vol. 81, No. 5. pp. 974-986.
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T1 - The first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder

T2 - Strong evidence of epistatic effects between loci on chromosomes 2q and 6q

AU - Jamra, Rami Abou

AU - Fuerst, Robert

AU - Kaneva, Radka

AU - Diaz, Guillermo Orozco

AU - Rivas, Fabio

AU - Mayoral, Fermin

AU - Gay, Eudoxia

AU - Sans, Sebastian

AU - González, Maria Jose

AU - Gil, Susana

AU - Cabaleiro, Francisco

AU - Del Rio, Francisco

AU - Perez, Fermin

AU - Haro, Jesus

AU - Auburger, Georg

AU - Milanova, Vihra

AU - Kostov, Christian

AU - Chorbov, Vesselin

AU - Stoyanova, Vessela

AU - Nikolova-Hill, Amelia

AU - Onchev, George

AU - Kremensky, Ivo

AU - Jablensky, Assen

AU - Schulze, Thomas G.

AU - Propping, Peter

AU - Rietschel, Marcella

AU - Nöthen, Markus M.

AU - Cichon, Sven

AU - Wienker, Thomas F.

AU - Schumacher, Johannes

PY - 2007

Y1 - 2007

N2 - We present the first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder (BPAD), using a large linkage data set (52 families of European descent; 448 participants and 259 affected individuals). Our results provide the strongest interaction evidence between BPAD genes on chromosomes 2q22-q24 and 6q23-q24, which was observed symmetrically in both directions (nonparametric LOD [NPL] scores of 7.55 on 2q and 7.63 on 6q; P <.0001 and , respectively, after a genomewide permutation procedure). The second-best BPAD interaction evidence P = .0001 was observed between chromosomes 2q22-q24 and 15q26. Here, we also observed a symmetrical interaction (NPL scores of 6.26 on 2q and 4.59 on 15q; and .0022, respectively). We covered the implicated regions by genotyping P = .0057 additional marker sets and performed a detailed interaction linkage analysis, which narrowed the susceptibility intervals. Although the heterogeneity analysis produced less impressive results (highest NPL score of 3.32) and a less consistent picture, we achieved evidence of locus heterogeneity at chromosomes 2q, 6p, 11p, 13q, and 22q, which was supported by adjacent markers within each region and by previously reported BPAD linkage findings. Our results provide systematic insights in the framework of BPAD epistasis and locus heterogeneity, which should facilitate gene identification by the use of more-comprehensive cloning strategies.

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