A genome screen of families at high risk for Hodgkin lymphoma: evidence for a susceptibility gene on chromosome 4

Hodgkin lymphoma (HL) has a strong familial component but no genes have yet been identified. We performed a genomewide linkage screen in 44 high risk HL families with a total of 254 individuals with DNA samples. Among these families, there were 95 HL cases and four cases of non-Hodgkin lymphoma (NHL) who were informative for linkage. The cases were characterised by a young age at diagnosis and an even gender ratio. In two-thirds of the families, the cases were siblings or cousins. We genotyped 1058 microsatellite markers with an average spacing of 3.5 cM, analysed the data using both non-parametric and parametric linkage analysis, and computed both two point and multi-point linkage statistics. The strongest linkage finding was on chromosome 4p near the marker D4S394. The lod score calculated by Genehunter Plus was 2.6 (nominal p=0.0002) when both HL and NHL individuals were considered affected. The mean identity by descent sharing among 35 affected sibling pairs was 72% in this region (nominal p=0.00007). The results are consistent with recessive inheritance. Other locations suggestive of linkage were found on chromosomes 2 and 11. The number of independent regions identified is more than expected by chance, although no one region met genomewide significance levels. These linkage findings represent the first step towards identifying one or more loci leading to susceptibility to HL and understanding its complex aetiology.