GENOME-WIDE LINKAGE SCAN IN A LARGE FAMILY WITH SUSPECTED GENETIC

							GENOME-WIDE LINKAGE SCAN IN A LARGE
  FAMILY WITH SUSPECTED GENETIC
    PREDISPOSITION TO CANCER


 Marroni F.1, Lipkin S.2, Benatti P.3, Pedroni M.3,
 Bailey-Wilson J.E.4, Collins F.4, Ponz de Leon
             M.3 and Presciuttini S.1,4
1 Università di Pisa, 2 University of California, 3 Università di Modena e Reggio
Emilia, 4 National Human Genome Research Institute, Baltimore
  Genome wide linkage analysis
• 392 markers ( 10cM average distance)
• 104 subjects, of which:
   – 31 completely typed
   – 9 partially typed
   – 54 untyped
• Three point linkage analysis using GAS and FASTLINK
• Parametric and non-parametric multipoint linkage analysis
  using GENEHUNTER
        Genome scan results

• A peak of lodscore  2.0 was obtained for
  two adjacent markers on chromosome 17
                     Genome scan results

            3

            2
Lod Score




            1

            0

            -1

            -2
                 0   20   40       60         80   100   120
                               Map position [cM]
Further studies on chromosome 17
• New sampling campaign: we obtained DNA
  samples from 10 new subjects
• Of them, one gave rise to mendelian
  inconsistencies and was therefore discarded
• For chromosome 17, typed subjects increased to
  46 (since three of the nine partially typed were not
  typed for Chrom17)
• In addition, three new markers were typed
  near the peak region
Further studies on chromosome 17
             3


             2
 Lod Score




             1


             0


             -1


             -2
                  0   20   40       60         80   100   120
                                Map position [cM]
                  Genome scan results
• 2 more interesting regions, with peaks of
  lodscore of  1.0
                  1.5
                    1
      Lod Score




                  0.5
                    0
                  -0.5
                   -1
                  -1.5
                         0   50           100    150
                             Map position (cM)
                   Genome scan results
• 2 more interesting regions, with peaks of
  lodscore of  1.0
                 1.5
                   1
     Lod Score




                 0.5
                   0
                 -0.5
                  -1
                 -1.5
                        0   50          100          150
                                 Map position (cM)
Power analysis for further studies
• We chose a real marker from one of the
  interesting regions
• 9 alleles: H=0.74
• In order to be able to run Fast-S-Link we
  had to renumber them to 6 (H=0.736)
                        Simulation results

                 1.0
                 0.8
                 0.6
Mean Lod Score




                                       0.843
                 0.4
                           0.462                Linkage
                 0.2                            No linkage
                 0.0
                           -0.359
                 -0.2                  -0.587
                 -0.4
                 -0.6
                        Original    Extended
                       Simulation results

                 2.5


                  2
Mean Lod Score




                 1.5


                  1


                 0.5


                  0
                       Real   Real+NewID   Real+All the living
               Conclusions
• We may obtain a substantial power increase
  for linkage analysis by adding to our study
  the newly sampled subjects
• This suggests that a possible option is to
  extend the typing of the entire marker set to
  the new subjects