Genome-wide scan and conditional analysis in bipolar disorder: evidence for genomic interaction in the National Institute of Mental Health genetics initiative bipolar pedigrees

McInnis, Melvin G.; Dick, Danielle M.; Willour, Virginia L.; Avramopoulos, Dimitrios; MacKinnon, Dean F.; Simpson, Sylvia G.; Potash, James B.; Edenberg, Howard J.; Bowman, Elizabeth S.; McMahon, Francis J.; Smiley, Carrie; Chellis, Jennifer L.; Huo, Yuqing; Diggs, Tyra L.; Meyer, Eric T.; Miller, Marvin J.; Matteini, Amy T.; Rau, N. Leela; DePaulo, J. Raymond; Gershon, Elliot S.; Badner, Judith A.; Rice, John P.; Goate, Alison M.; Detera‐Wadleigh, Sevilla D.; Nürnberger, John I.; Reich, Theodore; Zandi, Peter P.; Foroud, Tatiana

doi:10.1016/j.biopsych.2003.08.001

Cited by 77 publications

(35 citation statements)

References 60 publications

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“…Our results for the 20p12 region are consistent with several studies (McInnis et al, 2003;Fallin et al, 2004;Jones et al, 2007;Etain et al, 2009). By contrast, the 7q36 region has been reported in only two scans (Jones et al, 2007;Cassidy et al, 2009).…”

Section: Discussionsupporting

confidence: 93%

“…However, the 5q33 region, showing linkage in numerous independent reports (Edenberg et al 1997, Cichon et al, 2001Kelsoe et al, 2001;McInnis et al, 2003;Herzberg et al 2006;Jones et al, 2007) did not show linkage in our sample (p=0.04). Our results for the 20p12 region are consistent with several studies (McInnis et al, 2003;Fallin et al, 2004;Jones et al, 2007;Etain et al, 2009).…”

Section: Discussioncontrasting

confidence: 81%

“…BPI, BPII and MDE are defined as distinct entities in DSM-IV, which allows a high inter-rater concordance but which was not constructed to distinguish between different clinical entities depending on distinct genetic factors. Most genome-wide linkage scans have analyzed broad, intermediate and narrow phenotypes using a gradient from MDE to BPI through BPII (Garner et al, 2001;McInnis et al, 2003;Fallin et al, 2004;Schumacher et al, 2005;Zandi et al, 2007, Vazza et al, 2007Nwulia et al, 2007;Venken et al, 2007). This phenotypic classification may not be the most appropriate for defining phenotypes for the identification of linkage regions.…”

Section: Discussionmentioning

confidence: 99%

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European collaborative study of early‐onset bipolar disorder: Evidence for genetic heterogeneity on 2q14 according to age at onset

Mathieu

Dizier

Étain

et al. 2010

American J of Med Genetics Pt B

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Bipolar disorder has a genetic component, but the mode of inheritance remains unclear. A previous genome scan conducted in 70 European families led to detect eight regions linked to bipolar disease. Here, we present an investigation of whether the phenotypic heterogeneity of the disorder corresponds to genetic heterogeneity in these regions using additional markers and an extended sample of families. The MLS statistic was used for linkage analyses. The predivided sample test and the maximum likelihood binomial methods were used to test genetic homogeneity between early-onset bipolar type I (cut-off of 22 years) and other types of the disorder (later onset of bipolar type I and early-onset bipolar type II), using a total of 138 independent bipolar-affected sib-pairs. Analysis of the extended sample of families supports linkage in four regions (2q14, 3p14, 16p23, and 20p12) of the eight regions of linkage suggested by our previous genome scan. Heterogeneity testing revealed genetic heterogeneity between early and late-onset bipolar type I in the 2q14 region (P = 0.0001). Only the early form of the bipolar disorder but not the late form appeared to be linked to this region. This region may therefore include a genetic factor either specifically involved in the early-onset bipolar type I or only influencing the age at onset (AAO). Our findings illustrate that stratification according to AAO may be valuable for the identification of genetic vulnerability polymorphisms. (c) 2010 Wiley-Liss, Inc

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Section: Discussionsupporting

confidence: 93%

Section: Discussioncontrasting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

European collaborative study of early‐onset bipolar disorder: Evidence for genetic heterogeneity on 2q14 according to age at onset

Mathieu

Dizier

Étain

et al. 2010

American J of Med Genetics Pt B

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“…26,39 Support for this focus also comes from linkage and association studies in BPD 38,48,49 and from a meta-analysis of linkage studies in BPD 5 as well as from the presence of AHI1, a gene causing a severe neuropsychiatric disorder (Joubert Syndrome) in this location. Weaker positive results in linkage studies of SCZ and BPD were also demonstrated distal to this focus 28,40,47 and may represent poorer localization of the same locus. Suggestive evidence for linkage distal to F-4 was also demonstrated for a modifier gene in Huntington's disease.…”

Section: Discussionmentioning

confidence: 88%

“…McInnis et al 40 reported the results of a genome scan in 641 individuals affected with BPD, SA-bipolar type or recurrent major depression. The maximum multipoint NPL on 6q was 2.5 (P ¼ 0.008) at D6S311 (149 Mb) for a broad model.…”

Section: Schizophrenia Bipolar Othermentioning

confidence: 99%

Excitement and confusion on chromosome 6q: the challenges of neuropsychiatric genetics in microcosm

Kohn¹,

Lerer²

2005

Mol Psychiatry

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The search for genes that are implicated in the pathogenesis of schizophrenia (SCZ), bipolar disorder (BPD) and other complex neuropsychiatric phenotypes has yielded a plethora of positive findings, but has also engendered a substantial degree of confusion. Exciting findings include positive linkage results in a number of chromosomal regions and the identification of several genes that have been associated with SCZ and to a lesser extent with BPD. Confusing aspects include the difference between studies in localization of linkage peaks in the same chromosomal regions, raising the possibility that these regions may harbor more than one gene, the fact that positive linkage findings as well as associated genes appear in several cases to be shared by more than one disorder, and the failure to identify thus far the precise pathogenic variants in associated genes. Recent findings of linkage and association studies on chromosome 6q illustrate the current status of neuropsychiatric genetics in intriguing microcosm. Positive findings from linkage and association studies are reviewed in order to identify approaches that may help to settle apparent contradictions and allow an interpretation of the results that may prove useful in application to findings from other chromosomal regions. Not only SCZ and BPD but also other psychiatric and neurological phenotypes are considered. Taking a topographic approach, we identify five foci of positive findings on chromosome 6q and suggest that each may harbor gene(s) that confer susceptibility to SCZ or BPD or may modify their onset or clinical course. We further suggest that in searching for these genes the possibility that they may be implicated in more than one disorder should be taken into account. We also discuss the potential contribution of rare genetic variants identified in homogeneous, isolated populations to the subsequent identification of common variants in the same gene that contribute to disease susceptibility in outbred populations. Keywords: schizophrenia; bipolar disorder; chromosome 6q; molecular genetics; linkageThe last three decades have seen considerable advances in the field of psychiatric genetics. First, family twin and adoption studies conclusively established that genes play a major role in the etiology of many psychiatric disorders. Then, an increasing number of groups embarked on linkage studies aiming at localizing these genes. With ever improving technology, whole genome scans became the standard vehicle for these endeavors. Studies became more and more sophisticated, involving larger samples of carefully characterized affected individuals, using denser maps of markers and employing increasingly powerful statistical tools. Over the years, linkage studies have repeatedly implicated several chromosomal regions as linked to major psychiatric disorders, particularly schizophrenia (SCZ) and bipolar disorder (BPD) (for reviews, see Riley and McGuffin, 1 Berrettini,2 Kohn and Lerer 3 and Mathews and Reus 4 ). Recent meta-analyses of linkage studies have establi...

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Association of the human kainate receptor GluR7 gene (GRIK3) with recurrent major depressive disorder

Schiffer

Heinemann

2006

American J of Med Genetics Pt B

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The etiology of mood disorders remains elusive, despite our increasing understanding of the neurotransmitter systems and brain regions that are involved. We performed a large family-based association study to test if the human kainate receptor GluR7 gene (GRIK3) is associated with bipolar disorder (BP) or recurrent major depressive disorder (R-MDD). One hundred fiftythree multiplex BP families from the National Institute of Mental Health (NIMH) Genetics Initiative on Bipolar Disorder were analyzed with the transmission disequilibrium test (TDT). We detected a significant linkage disequilibrium (LD) indicated by preferential maternal transmission of the GluR7 S310 allele to R-MDD patients (P ¼ 0.012), but not to bipolar I disorder (BPI) patients (P ¼ 1.00). We performed a second independent study by applying the TDT in 81 parentoffspring triads from families that inherit recurrent early-onset major depressive disorder (RE-MDD). The results from this second study showed only a suggestive maternal association (P ¼ 0.068). Our findings imply that the GluR7 gene is a susceptibility factor in R-MDD and that the glutamatergic receptor system plays a critical role in the disease etiology.

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Genome-wide scan and conditional analysis in bipolar disorder: evidence for genomic interaction in the National Institute of Mental Health genetics initiative bipolar pedigrees

Cited by 77 publications

References 60 publications

European collaborative study of early‐onset bipolar disorder: Evidence for genetic heterogeneity on 2q14 according to age at onset

European collaborative study of early‐onset bipolar disorder: Evidence for genetic heterogeneity on 2q14 according to age at onset

Excitement and confusion on chromosome 6q: the challenges of neuropsychiatric genetics in microcosm

Association of the human kainate receptor GluR7 gene (GRIK3) with recurrent major depressive disorder

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