Implications of comorbidity and ascertainment bias for identifying diseasegenes

Comorbidity, the co-occurrence of disorders, is frequently observed to occu r at higher rates in clinically ascertained samples than in population-base d samples, An explanation for this finding is that subjects suffering from multiple illnesses are more likely to seek medical care and receive a diagn ostic evaluation We refer to the component of the comorbidity between illne sses due to such ascertainment bias as "spurious comorbidity." When spuriou s comorbidity is present, an apparent association between a candidate locus and the phenotype of interest may actually be attributable to an associati on between the locus and a comorbid phenotype, This phenomenon, which we ca ll "spurious comorbidity bias," could thus produce misleading association f indings. In this article, we describe this phenomenon and demonstrate that it may produce marked bias in the conclusions of family-based association s tudies. Because of the extremely high rates of comorbidity among psychiatri c disorders in clinical samples, this problem may be particularly salient f or genetic studies of neuropsychiatric disorders, We conclude that ascertai nment bias may contribute to the frequent difficulty in replicating candida te gene study findings in psychiatry. (C) 2000 Wiley-Liss, Inc.