The First Genomewide Interaction and Locus-Heterogeneity Linkage Scan in Bipolar Affective Disorder: Strong Evidence of Epistatic Effects between Loci.

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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 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, George Onchev, Ivo Kremensky, Assen Jablensky, Thomas G. Schulze, Peter Propping, Marcella Rietschel, Markus M. Nöthen, Sven Cichon, Thomas F. Wienker, Johannes Schumacher The American Journal of Human Genetics Volume 81, Issue 5, Pages 974-986 (November 2007) DOI: 10.1086/521690 Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 1 Genomewide interaction scan for BPAD. The different levels of ΔNPL scores are presented using different colors: red indicates ΔNPL scores >4; yellow indicates ΔNPL scores >3; green indicates ΔNPL scores >2; light blue indicates ΔNPL scores >1; dark blue indicates ΔNPL scores >0; black indicates ΔNPL scores <0. The American Journal of Human Genetics 2007 81, 974-986DOI: (10.1086/521690) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 2 Three-dimensional ΔNPL plot for the BPAD interaction between chromosomes 2q22-q24 and 6q23-q24. The 1-LOD intervals are given at the bottom of the plot, in blue. Genetic-marker positions are determined from the deCODE Genetics sex-averaged map, and ΔNPL scores are indicated by red lines. A, Interaction on chromosome 2q22-q24, presented using STRs on 6q as conditional markers (highest ΔNPL score 6.69). B, Interaction on chromosome 6q23-q24, presented using STRs on 2q as conditional markers (highest ΔNPL score 4.84). The American Journal of Human Genetics 2007 81, 974-986DOI: (10.1086/521690) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 3 Proportions of families contributing to the BPAD interaction. Each unit represents one linkage family (total n=52). A, BPAD interaction between chromosomes 2q22-q24 (D2S1353, D2S381, D2S222, D2S321, and D2S2950) and 6q23-q24 (D6S1587, D6S1626, D6S1699, D6S403, and D6S1569). Red indicates 10 families assigned a weightPROP factor >0 at markers within the top 10 interaction interval on 2q22-q24 and assigned a weightPROP factor of 0 at markers within the top 10 interaction interval on 6q23-q24. Blue indicates 14 families assigned a weightPROP factor >0 at markers on 6q23-q24 and assigned a weightPROP factor of 0 at markers on 2q22-q24. Purple indicates 22 families assigned a weightPROP factor >0 at markers on 2q22-q24 and at markers on 6q23-q24. Gray indicates six families assigned a weightPROP factor of 0 at all markers on 2q22-q24 and on 6q23-q24. B, Proportions of families with strong contribution—defined by weightPROP factors >1—to the BPAD interaction between chromosomes 2q22-q24 and 6q23-q24. Red indicates eight families assigned a weightPROP factor >1 at markers on 2q22-q24 and assigned a weightPROP factor of 0 at markers on 6q23-q24. Blue indicates eight families assigned a weightPROP factor >1 at markers on 6q23-q24 and assigned a weightPROP factor of 0 at markers on 2q22-q24. Purple indicates 11 families assigned a weightPROP factor >1 at markers on 2q22-q24 and at markers on 6q23-q24. Gray indicates 19 families assigned a weightPROP factor >0 at markers on 2q22-q24 (right) or at markers on 6q23-q24 (left). Black indicates six families assigned a weightPROP factor of 0 at all markers on 2q22-q24 and on 6q23-q24. C, BPAD interaction between chromosomes 2q22-q24 (D2S1353, D2S2395, D2S2950, D2S381, or D2S222) and 15q26 (STR15-980, STR15-994, or D15S107). Red indicates 15 families assigned a weightPROP factor >0 at markers on 2q22-q24 and assigned a weightPROP factor of 0 at markers on 15q26. Blue indicates 14 families assigned a weightPROP factor >0 at markers on 15q26 and assigned a weightPROP factor of 0 at markers on 2q22-q24. Purple indicates 17 families assigned a weightPROP factor >0 at markers on 2q22-q24 and at markers on 15q26. Gray indicates six families assigned a weightPROP factor of 0 at all markers within the top 10 interaction interval on 2q22-q24 and on 15q26. D, Proportions of families with strong contribution—defined by weightPROP factors >1—to the BPAD interaction between chromosomes 2q22-q24 and 15q26. Red indicates 12 families assigned a weightPROP factor >1 at markers on 2q22-q24 and assigned a weightPROP factor of 0 at markers on 15q26. Blue indicates four families assigned a weightPROP factor >1 at markers on 15q26 and assigned a weightPROP factor of 0 at markers on 2q22-q24. Purple indicates 11 families assigned a weightPROP factor >1 at markers on 2q22-q24 and at markers on 15q26. Gray indicates 22 families assigned a weightPROP factor of >0 at markers on 2q22-q24 (right) or at markers on 15q26 (left). Black indicates six families assigned a weightPROP factor of 0 at all markers within the top 10 interaction interval on 2q22-q24 and on 15q26. The American Journal of Human Genetics 2007 81, 974-986DOI: (10.1086/521690) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 4 Three-dimensional ΔNPL plot for the BPAD interaction between chromosome 2q22-q24 and 15q26. The 1-LOD intervals are given at the bottom of the plot, in blue. Genetic-marker positions are determined from the deCODE Genetics sex-averaged map, and ΔNPL scores are indicated by red lines. A, Interaction on chromosome 15q26, presented using STRs on 2q as conditional markers (highest ΔNPL score 3.74). B, Interaction on chromosome 2q22-q24, presented using STRs on 15q as conditional markers (highest ΔNPL score 5.62). The American Journal of Human Genetics 2007 81, 974-986DOI: (10.1086/521690) Copyright © 2007 The American Society of Human Genetics Terms and Conditions