Linkage of human narcolepsy with HLA association to chromosome 4p13-q21.

Although narcolepsy is highly associated with human leukocyte antigen (HLA) DQ6/DQB1*0602 and/or DR2/DRB1*1501, most individuals with the HLA haplotype are free of narcolepsy. This indicates that HLA alone makes a relatively small contribution to the development of narcolepsy and that a non-HLA gene(s) can contribute to the genetic predisposition even in narcoleptic cases with HLA association. We conducted a genome-wide linkage search for narcolepsy in eight Japanese families with 21 DR2-positive patients (14 narcoleptic cases with cataplexy and 7 cases with an incomplete form of narcolepsy). A lod score of 3.09 suggested linkage to chromosome 4p13-q21. A lod score of 1.53 was obtained at the HLA-DRB1 locus, though this lod score may be biased since all the affected patients and many of the family members were DR2-positive. No other loci including hypocretin, hypocretin receptor 1, and hypocretin receptor 2 had lod scores greater than 1.0. The present study suggests that chromosome 4p13-q21 contains a second locus for HLA-associated human narcolepsy.