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; Díaz, Guillermo Orozco; Rivas, Fabio; Mayoral, Fermín; Gay, Eudoxia; Sans, Sebastian; Gonzalez, Maria J.; Gil, Susana María; Cabaleiro, Francisco; Río, Francisco del; Pérez, Fermín; Haro, Jesus; Auburger, Georg; Milanova, Vihra; Kostov, Christian; Chorbov, Vesselin M.; Stoyanova, В.; Nikolova-Hill, Amelia; Onchev, Georgi; Kremensky, Ivo; Jablensky, Assen; Schulze, Thomas G.; Propping, Peter; Rietschel, Marcella; Nöthen, Markus M.; Cichon, Sven; Wienker, Thomas F.; Schumacher, Johannes

doi:10.1086/521690

Cited by 38 publications

(21 citation statements)

References 48 publications

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“…Weak evidence was obtained for the 2q locus in the separate families, but no significant values were produced by the joint pedigree. While a recent re-analysis of the family sample used in our initial linkage study [Schumacher et al, 2005] suggests that epistatic interactions between the 2q22-q24 and 6q23-q24 loci play a role in susceptibility to BPAD [Abou Jamra et al, 2007], our results do not support 2q (as well as 6q, see below) as candidate regions for further studies in the Gypsy population.…”

Section: Discussioncontrasting

confidence: 89%

Bipolar disorder in the Bulgarian Gypsies: Genetic heterogeneity in a young founder population

Kaneva

Milanova

Angelicheva

et al. 2008

American J of Med Genetics Pt B

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We report the results of follow-up analyses of 12 genomic regions showing evidence of linkage in a genome-wide scan (GWS) of Gypsy families with bipolar affective disorder (BPAD). The Gypsies are a young founder population comprising multiple genetically differentiated sub-isolates with strong founder effect and limited genetic diversity. The BPAD families belong to a single sub-isolate and are connected by numerous inter-marriages, resulting in a super-pedigree with 181 members. We aimed to re-assess the positive GWS findings and search for evidence of a founder susceptibility allele after the addition of newly recruited subjects, some changes in diagnostic assignment, and the use of denser genetic maps. Linkage analysis was conducted with SimWalk2, accommodating the full complexity of pedigree structure and using a conservative narrow phenotype definition (BPAD only). Six regions were rejected, while 1p36, 13q31, 17p11, 17q21, 6q24, and 4q31 produced nominally significant results in both the individual families and the super-pedigree. Haplotypes were reconstructed and joint tests for linkage and association were done for the most promising regions. No common ancestral haplotype was identified by sequencing a strong positional and functional candidate gene (GRM1) and additional STR genotyping in the top GWS region, 6q24. The best supported region was a 12 cM interval on 4q31, also implicated in previous studies, where we obtained significant results in the super-pedigree using both SimWalk2 (P = 0.004) and joint Pseudomarker analysis of linkage and linkage disequilibrium (P = 0.000056). The size of the region and the characteristics of the Gypsy population make it suitable for LD mapping.

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Section: Discussioncontrasting

confidence: 89%

Bipolar disorder in the Bulgarian Gypsies: Genetic heterogeneity in a young founder population

Kaneva

Milanova

Angelicheva

et al. 2008

American J of Med Genetics Pt B

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“…The search was performed in pub med for every chromosome separately with the key words: “Bipolar disorder, genetics, linkage, chromosome 1…X” and “Migraine, genetics, linkage, chromosome 1…X”, Table 3 displays all linkage loci that have been significantly or suggestively found in migraine linkage studies (Gardner et al, 1997; Nyholt et al, 1998a,b, 2000; Jones et al, 2001; Carlsson et al, 2002; Wessman et al, 2002; Lea et al, 2002; Björnsson et al, 2003; Soragna et al, 2003; Cader et al, 2003; Nyholt et al, 2005; Russo et al, 2005; Lea et al, 2005; Anttila et al, 2006), and the bipolar linkage studies (Savitz et al, 2007; Jamra et al, 2007; Zandi et al, 2007; Goes et al, 2007; Cassidy et al, 2007; Kerner et al, 2007; Jones et al, 2007; Etain et al, 2006; Marcheco-Teruel et al, 2006; Tomàs et al, 2006; Mukherjee et al, 2006; Schumacher et al, 2005; Hamshere et al, 2005; Lambert et al, 2005; McQueen et al, 2005; Kealey et al, 2005; Lin et al, 2005; Macgregor et al, 2004; Middleton et al, 2004; Fallin et al, 2004; Curtis et al, 2003; McInnis et al, 2003; Willour et al, 2003; Ewald et al, 2003; Ekholm et al, 2003; Ewald et al, 2002; Ekholm et al, 2002; Bailer et al, 2002; Dick et al, 2002; Cichon et al, 2001; Kelsoe et al, 2001; Radhakrishna et al, 2001; Detera-Wadleigh et al, 1999; Morissette et al, 1999; Ginns et al, 1998; Ewald et al, 1998; Detera-Wadleigh et al, 1997; Edenberg et al, 1997; Blackwood et al, 1996; Turecki et al, 1995; Pekkarinen et al, 1995) that have demonstrated overlapping or closely related linkage to these migraine loci. In addition we compared linkage studies in BPAD to the identified genes in FHM, and the BPAD (Jamra et al, 2007; Zandi et al, 2007; Hamshere et al, 2005; Middleton et al, 2004; Fallin et al, 2004; …”

Section: Discussionmentioning

confidence: 99%

A genome-wide linkage study of bipolar disorder and co-morbid migraine: Replication of migraine linkage on chromosome 4q24, and suggestion of an overlapping susceptibility region for both disorders on chromosome 20p11

Oedegaard

Greenwood

Lunde

et al. 2010

Journal of Affective Disorders

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Migraine and Bipolar Disorder (BPAD) are clinically heterogeneous disorders of the brain with a significant, but complex, genetic component. Epidemiological and clinical studies have demonstrated a high degree of co-morbidity between migraine and BPAD. Several genome-wide linkage studies in BPAD and migraine have shown overlapping regions of linkage on chromosomes, and two functionally similar voltage-dependent calcium channels CACNA1A and CACNA1C have been identified in familial hemiplegic migraine and recently implicated in two whole genome BPAD association studies, respectively. We hypothesized that using migraine co-morbidity to look at subsets of BPAD families in a genetic linkage analysis would prove useful in identifying genetic susceptibility regions in both of these disorders. We used BPAD with co-morbid migraine as an alternative phenotype definition in a re-analysis of the NIMH Bipolar Genetics Initiative wave 4 data set. In this analysis we selected only those families in which at least two members were diagnosed with migraine by a doctor according to patients' reports. Nonparametric linkage analysis performed on 31 families segregating both BPAD and migraine identified a linkage signal on chromosome 4q24 for migraine (but not BPAD) with a peak LOD of 2.26. This region has previously been implicated in two independent migraine linkage studies. In addition we identified a locus on chromosome 20p11 with overlapping elevated LOD scores for both migraine (LOD = 1.95) and BPAD (LOD = 1.67) phenotypes. This region has previously been implicated in two BPAD linkage studies, and, interestingly, it harbors a known potassium dependant sodium/calcium exchanger gene, SLC24A3, that plays a critical role in neuronal calcium homeostasis. Our findings replicate a previously identified migraine linkage locus on chromosome 4 (not co-segregating with BPAD) in a sample of BPAD families with co-morbid migraine, and suggest a susceptibility locus on chromosome 20, harboring a gene for the migraine/BPAD phenotype. Together these data suggest that some genes may predispose to both bipolar disorder and migraine.

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“…Gene-gene interactions (epistasis) may play a major role in the aetiology of complex human diseases, and some argue that attempts to unravel the genetic basis of such disorders will fail if epistasis is ignored (Frankel & Schork, 1996). Searching for epistatic effects at a genome-wide level is an ambitious goal that has so far met with limited success in BPD (Abou Jamra et al, 2007, Ferreira et al, 2008). In contrast, a burgeoning literature now exists suggesting possible gene-environment effects in psychiatric disorders (Caspi et al, 2002, Caspi et al, 2003).…”

Section: Alternative Strategies For Identifying Genetic Risk Factorsmentioning

confidence: 99%

The genetics of bipolar disorder

2009

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Bipolar disorder is a mood disorder characterized by impairing episodes of mania and depression. Twin studies have established that bipolar disorder is among the most heritable of medical disorders and efforts to identify specific susceptibility genes have intensified over the past two decades. The search for genes influencing bipolar disorder has been complicated by a paucity of animal models, limited understanding of pathogenesis, and the genetic and phenotypic complexity of the syndrome. Linkage studies have implicated several chromosomal regions as harboring relevant genes, but results have been inconsistent. It is now widely accepted that the genetic liability to bipolar disorder reflects the action of many genes of individually small effect, a scenario for which linkage studies are poorly suited. Thus, association studies, which are more powerful for the detection of modest effect loci, have become the focus of gene-finding research. A large number of candidate genes, including biological candidates derived from hypotheses about the pathogenesis of the disorder and positional candidates derived from linkage and cytogenetic studies, have been evaluated. Several of these genes have been associated with the disorder in independent studies (including BDNF, DAOA, DISC1, GRIK4, SLC6A4, and TPH2), but none has been established. The clinical heterogeneity of bipolar disorder and its phenotypic and genetic overlap with other disorders (especially schizophrenia, schizoaffective disorder, and major depressive disorder) has raised questions about the optimal phenotype definition for genetic studies. Nevertheless, genomewide association analysis, which has successfully identified susceptibility genes for a variety of complex disorders, has begun to implicate specific genes for bipolar disorder (DGKH, CACNA1C, ANK3). The polygenicity of the disorder means that very large samples will be needed to detect the modest effect loci that likely contribute to bipolar disorder. Detailed genetic dissection of the disorder may provide novel targets (both pharmacologic and psychosocial) for intervention.

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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

Cited by 38 publications

References 48 publications

Bipolar disorder in the Bulgarian Gypsies: Genetic heterogeneity in a young founder population

Bipolar disorder in the Bulgarian Gypsies: Genetic heterogeneity in a young founder population

A genome-wide linkage study of bipolar disorder and co-morbid migraine: Replication of migraine linkage on chromosome 4q24, and suggestion of an overlapping susceptibility region for both disorders on chromosome 20p11

The genetics of bipolar disorder

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