A possible susceptibility locus for bipolar affective disorder in chromosomal region 10q25–q26

Abstract

In an attempt to identify susceptibility loci for bipolar affective disorder, we are currently conducting a systematic genome screen with highly polymorphic microsatellite markers at an average marker spacing of 10 cM in a series of 75 families, comprising 66 families from Germany, eight families from Israel, and one family from Italy. The families were ascertained through index cases with bipolar affective disorder. The distribution of diagnoses is as follows: 126 individuals with bipolar I disorder, 40 with bipolar II disorder, 14 with schizoaffective disorder of the bipolar type, 40 individuals with recurrent unipolar depression, 51 with a minor psychiatric diagnosis, and two individuals with a diagnosis of schizophrenia. One hundred and seventy-one individuals are unaffected. Here, we present results from chromosome 10. Linkage analyses using a total of 33 microsatellite markers with parametric and non-parametric methods provided evidence for linkage at chromosomal region 10q25-q26. The highest two-point LOD score (2.86, = 0.05) was obtained for D10S217 using a dominant genetic model and a broad definition of affection status. The GENEHUNTER program localized the putative susceptibility locus within a ca 15-cM interval between markers D10S1483 and D10S217 with a maximum NPL(all) score of 3.12 (P = 0.0013). Positive linkage findings that have been reported by two independent studies further support the hypothesis of a susceptibility gene for bipolar affective disorder on 10q25-q26. Molecular Psychiatry (2001) 6, 342-349.Bipolar affective disorder (BPAD), also known as manic depressive illness, is characterized by severe aberrant mood swings in alternating periods of mania and depression. The disorder is common with a lifetime prevalence of about 1% in all human populations and results in high costs in terms of morbidity as well as mortality. BPAD is substantially responsive to drug treatment, but episodes tend to recur throughout life. Although the etiology and pathophysiology is widely unknown, family, twin and adoption studies argue for a strong genetic determination of the disease. 1 Theories concerning the possible involvement of multiple genes of small effect and/or the occurrence of major allelic effects in epistasis have been advanced. In order to identify genes predisposing to BPAD, in the absence of substantial molecular pathophysiological knowledge, linkage analysis is one of the best available methods. Early linkage studies were conducted in large families and were based on the implausible assumption that a single major gene was responsible for the disorder: loci for BPAD on the X chromosome 2-4 and on chromosome 11p15 5 were reported and attracted considerable attention, but have not withstood molecular studies in independent samples 6-8 as well as updated and extended analyses by the original groups. 9,10 The reason for these inconclusive results were, for the most part, problems concerning diagnosis, ascertainment of pedigrees, statistical analysis, and lack of availability of dense genetic link...

Preliminary evidence for linkage to chromosome 1q31‐32, 10q23.3, and 16p13.3 in a South African cohort with bipolar disorder

“…Kelsoe et al [2001] and McInnis et al [2003] also implicated this region of the chromosome. It is unclear if our results together with those of Rice et al [1997], Park et al [2004], and Fallin et al [2003] are reflecting linkage to the same susceptibility locus implicated by Cichon et al [2001], Kelsoe et al [2001], and McInnis et al [2003].…”

“…The most promising of these results were those of Cichon et al [2001] who obtained a maximum parametric LOD score of 2.86 under a broad affection status and dominant model of inheritance, and a maximum Z score of 3.12 at 125 Mb. Kelsoe et al [2001] and McInnis et al [2003] also implicated this region of the chromosome.…”

Genome‐scan for bipolar disorder with sib‐pair families in the Sardinian population: A new susceptibility locus on chromosome 1p22–p21?

“…Interestingly, the D1S216 marker at 1p31.1 is close to the 1p22-p21 region and linkage of this region to BD using the D1S216 marker has previously been reported [Ewald et al, 1998a]. The regions identified in the present study in other chromosomes that have already been linked to BD were located on chromosomes 2q24 [Zandi et al, 2007]; 5p15, a region containing the Dopamine Transporter gene, with the same D5S417 marker [Kelsoe et al, 2001]; 7q34 [Liu et al, 2003]; 8p23 [Ophoff et al, 2002;Walss-Bass et al, 2006] and 8q24 [Cichon et al, 2001b;Badenhop et al, 2002]; 9q21 [Friddle et al, 2000] with the D9S264 marker used in the former study only 0.33 Mb apart from the D9S167 marker yielding a positive result for the present genome scan; 10q26 [Kelsoe et al, 2001;Cichon et al, 2001a;Ewald et al, 2002;McInnis et al, 2003b]; 11p15, a region harboring the Tyrosine Hydroxylase and DRD4 genes [Smyth et al, 1996;Malafosse et al, 1997;Serretti et al, 2000;McInnis et al, 2003b]; 21q21 [Cassidy et al, 2007].Besides the markers in the 1p21-p22 region showing NPLs above 3.4, several other markers were characterized by a NPL between 2.5 and 3 and a P-value <0.005, such as D1S2752 at 1p32; D7S798 at 7q34; D8S1832 at 8q24, all regions previously linked to BD, and the marker D1S214 at 1p36.31, a region that has shown suggestive linkage to BD in the present study only (Table III).In order to further exploit these results, we reanalyzed the genotyping data using allele frequency estimations calculated by the MERLIN software [Abecasis et al, 2002]. We reasoned that, since evaluated allele frequencies are closer to the real marker frequencies in the Sardinian population and are more conservative for estimating linkage, this approach allows for further assessing the relevance of the genome scan results.…”

A genome-wide scan shows significant linkage between bipolar disorder and chromosome 12q24.3 and suggestive linkage to chromosomes 1p22–21, 4p16, 6q14–22, 10q26 and 16p13.3

“…61 On chromosome 10q26 a positive lod score was found at D10S217 in family 4 and the third highest NPL-all score in family 4 anywhere in the genome was 2.60 (P-value 0.01013), 2 cM proximal to D10S217. This region has received some support from other studies of bipolar disorder [69][70][71] and schizophrenia. 72 On chromosome 4p16 we have previously reported a lod score of 2.00 at a theta of 0.03 from D4S394.…”