A Genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases

Damini Jawaheer, Michael F. Seldin, Christopher I. Amos, Wei V. Chen, Russell Shigeta, Joanita Monteiro, Marlene Kern, Lindsey A. Criswell, Salvatore Albani, J. Lee Nelson, Daniel O. Clegg, Richard Pope, Harry W. Schroeder, S. Louis Bridges, David S. Pisetsky, Ryk Ward, Daniel L. Kastner, Ronald L. Wilder, Theodore Pincus, Leigh F. CallahanDonald Flemming, Mark H. Wener, Peter K. Gregersen

Research output: Contribution to journalArticlepeer-review

316 Scopus citations


Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with a complex genetic component. We report the first major genomewide screen of multiplex families with RA gathered in the United States. The North American Rheumatoid Arthritis Consortium, using well-defined clinical criteria, has collected 257 families containing 301 affected sibling pairs with RA. A genome screen for allele sharing was performed, using 379 microsatellite markers. A nonparametric analysis using SIBPAL confirmed linkage of the HLA locus to RA (P < .00005), with λHLA = 1.79. However, the analysis also revealed a number of non-HLA loci on chromosomes 1 (D1S235), 4 (D4S1647), 12 (D12S373), 16 (D16S403), and 17 (D17S1301), with evidence for linkage at a significance level of P < .005. Analysis of X-linked markers using the MLOD method from ASPEX also suggests linkage to the telomeric marker DXS6807. Stratifying the families into white or seropositive subgroups revealed some additional markers that showed improvement insignificance over the full data set. Several of the regions that showed evidence for nominal significance (P < .05) in our data set had previously been implicated in RA (D16S516 and D17S1301) or in other diseases of an autoimmune nature, including systemic lupus erythematosus (D1S235), inflammatory bowel disease (D4S1647, D5S1462, and D16S516), multiple sclerosis (D12S1052), and ankylosing spondylitis (D16S516). Therefore, genes in the HLA complex play a major role in RA susceptibility, but several other regions also contribute significantly to overall genetic risk.

Original languageEnglish (US)
Pages (from-to)927-936
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number4
StatePublished - 2001

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)


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