Map of candidate genes and STSs on 18p11.2, a bipolar disorder and schizophrenia susceptibility region

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Sir – Linkage and association studies suggest an overlap of bipolar disorder and schizophrenia susceptibility regions on chromosome 18p.1,2,3,4 Fine genetic mapping revealed the highest evidence of linkage at 18p11.2.5 Located in this region are GNAL and IMPA2, alleles of which have been associated with schizophrenia,2,4 raising the possibility of at least one predisposing gene for a major psychiatric disorder in the region. But, if neither GNAL nor IMPA2 is the susceptibility gene, then it is essential to identify and systematically scrutinize all candidate genes on 18p11.2 for risk-conferring mutations. To investigate this region further, we constructed an array of overlapping BAC and PAC clones spanning 8 cM region flanked by pter-D18S464 and D18S360E-pcen. Included in the contig were 16 BACs and four PACs upon which 47 sequence tag sites (STSs) were mapped through PCR. A total of 29 new STSs generated from BAC/PAC insert ends were used to facilitate chromosome walking and ordering of clones.

The availability of the first draft of the human genome sequence6,7 permits determination of the position and order of candidate genes and new STSs. By using these sequences to conduct BLAST analysis on the National Center for Biotechnology Information (NCBI) database,8 we found that the D18S464 and D18S360E interval is covered by six contigs, arranged in the following order: pter—NT_010870 (901 kb)—NT_025037 (229.7 kb)—NT_019631 (969.3 kb)—NT_010956 (1139 kb)— NT_010918 (334.8 kb)—NT_010859 (1966 kb)—pcen (Table 1Table 1bTable 1c).

Table 1 Candidate genes and STSs on 18p11.2

Here, we present the map of 18p11.2 using the University of California-Santa Cruz (UCSC) Genome Browser version April 1, 20019 as template (Table 1aTable 1bTable 1c). We included in this map 19 known and hypothetical full-length mRNAs, nine ESTs, 13 polymorphic STSs and 29 ends of BAC/PAC clones that we isolated (Table 1aTable 1bTable 1c). Not shown are at least 50 additional predicted exons on 18p11.2.9,10

BLASTN analyses were conducted to identify the cognate BAC clones for the genes/STSs/clone ends, and the corresponding contigs that contain these clones (Table 1aTable 1bTable 1c). Except for NT_010918, the contigs included at least one of our BAC/PAC clones (Table 1aTable 1bTable 1c). Mapping inconsistencies were displayed by SHGC-32292, SHGC-34655 and D18S71, loci that map to NT_010918, a contig that does not contain any of our clones. Similar mapping inconsistencies were exhibited by WI-11680 and D18S378. Based on the position of our clones in the contigs, the gaps in our map most likely occur in NT_010918 and the distal halves of NT_010870 and NT_019631. Despite the gaps and some inversion in the order of loci, overall our map matches well with that in Table 1aTable 1bTable 1c.

The distance between D18S464 and D18S360E is 4.536 Mb. We determined the position of the BAC/PAC ends and other STSs by performing a DNA BLAT search, a feature in the UCSC Genome Browser9 (Table 1aTable 1bTable 1c). GNAL and IMPA2 are within ±100 kb, and these sequences do overlap (Table 1aTable 1bTable 1c). We found a similar estimate of the physical distance between these genes from PCR-based mapping data and pulsed field gel electrophoresis of BAC/PAC Not I fragments. These estimates contrast with >300 kb separation between these two genes as shown in NT_010956. Gaps and ambiguous locations still exist in this and other contigs.

The evidence of association in GNAL and IMPA2 increases the importance of nearby genes encoded by NT_010956. CHMP 1.5 and BC002877 are examples (Table 1aTable 1bTable 1c). BLASTP analysis on BC002877 shows motifs similar to DNA repair exonuclease and a yeast cell division control protein. Not shown here are five other predicted exons in this contig, one of which shows homology to NF-kappa-B2.9 D18S53, a marker that yielded suggestive linkage to bipolar disorder and schizophrenia1,2 resides in this contig.

D18S37, a marker linked to bipolar disorder1,3 maps to NT_010859. Centromeric of this marker are C18ORF1, a gene we previously cloned,11 and two melanocortin receptors. Located distally is AFMA058YG5, a marker that showed the strongest evidence of allele sharing in mood disorder sib-pairs in our study (unpublished data). This contig and the region closer to the centromere seem to be gene-rich9 (Table 1aTable 1bTable 1c). Linkage disequilibrium mapping and screening of these genes is warranted to hunt for susceptibility alleles for mood disorders.

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Correspondence to S D Detera-Wadleigh.

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