Recent human genetic studies have consistently shown that mutations in the same gene or same genomic region can increase the risk of a broad range of complex neuropsychiatric disorders. Despite the steadily increasing number of examples of such nonspecific effects on risk, the underlying biological causes remain mysterious. Here we investigate the phenomenon of such nonspecific risk by identifying Mendelian disease genes that are associated with multiple diseases and explore what is known about the underlying mechanisms in these more 'simple' examples. Our analyses make clear that there are a variety of mechanisms at work, emphasizing how challenging it will be to elucidate the causes of nonspecific risk in complex disease. Ultimately, we conclude that functional approaches will be critical for explaining the causes of nonspecific risk factors discovered by human genetic studies of neuropsychiatric disorders.