Additional, physically ordered markers increase linkage signal for bipolar disorder on chromosome 18q22.

BACKGROUND

We recently reported evidence of linkage of bipolar disorder to chromosome 18q, with a paternal logarithm of odds (LOD) score of 4.67 (p =.004) in a clinically defined subset of families. Like other linkage studies, we had to rely on imprecise genetic maps to establish the marker order. Here, we test for linkage in the same sample with a denser set of markers, now physically ordered according to the draft sequence of the human genome.

METHODS

Families were ascertained through probands with bipolar I disorder and diagnosed with reliable methods. Genotypes were generated for 12 microsatellite markers within an 11-centimorgan (cM) region of chromosome 18q22. Multipoint affected sib-pair linkage analysis was performed in a set of 16 nuclear families.

RESULTS

The additional markers significantly increased the total genetic information extracted from our sample. We also observed an increase in the LOD score (to 5.42, p =.0066) and linkage resolution. The approximate 1-LOD support interval is now 9 male cM.

CONCLUSIONS

The results strengthen our previous findings and further define a region suitable for genetic fine-mapping analysis on chromosome 18q. Our data suggest that a dense set of markers, when physically ordered, can increase the informational value of genetic linkage signals.