Systemic lupus erythematosus (SLE) is characterized by various IgG autoreactivities, among which anti-Ro/SS-A is particularly pathology-associated and early detectable. SLE also shows significant familial aggregation, but genetic factors are not well understood and remain controversial for disease-associated IgG. Here we report that IgM anti-Ro showed a uniquely high degree of heritability in a study of SLE-affected families. Unlike IgM anti-La or anti-dsDNA, IgM anti-Ro was also significantly correlated to IgG anti-Ro among SLE patients, as well as to IgG anti-La and anti-dsDNA. We conclude that largely genetically determined, thus natural IgM anti-Ro-bearing precursor B-cells, may be an important factor for class switching and determinant spreading in early phases of SLE pathogenesis. Furthermore, we found unexpected sex differences in isotype/specificity correlations among SLE-unaffected relatives and control subjects, which could help understand the strong gender bias associated with SLE. We propose that the study of such correlation structures may reveal characteristic spreading pathways relevant for human SLE.