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Strabismus has been known to have a significant genetic component, but the mode of inheritance and the identity of the relevant genes have been enigmatic. This paper reports linkage analysis of nonsyndromic strabismus. The principal results of this study are: (i) the demonstrated feasibility of identifying and recruiting large families in which multiple members have (or had) strabismus; (ii) the linkage in one large family of a presumptive strabismus susceptibility locus to 7p22.1 with a multipoint logarithm of odds score of 4.51 under a model of recessive inheritance; and (iii) the failure to observe significant linkage to 7p in six other multiplex families, consistent with genetic heterogeneity among families. These findings suggest that it will be possible to localize and ultimately identify strabismus susceptibility genes by linkage analysis and mutation screening of candidate genes.linkage ͉ whole genome scan ͉ complex trait ͉ ophthalmic genetics S trabismus (misalignment of the eyes; also referred to as ''squint'') is one of the most common ocular disorders in humans, affecting 1-4% of the population (1). It is frequently associated with amblyopia (uniocular visual neglect), a leading cause of visual impairment in children and young adults. The familial clustering of strabismus has been recognized since antiquity. For example, Hippocrates stated that ''children of parents having distorted eyes squint also for the most part'' (1).Numerous twin and family studies point to a significant genetic component in the etiology of strabismus (summarized in refs. 1-4). Summing the data from 11 published twin studies shows that, among 206 monozygotic and 130 dizygotic twin pairs in which one member of the twin pair had strabismus, 73% of monozygotic twin pairs were concordant for strabismus, whereas only 35% of dizygotic twin pairs were concordant for strabismus. We note that the degree of concordance among dizygotic twin pairs is higher than the Ϸ10-15% typically reported for siblings; this may reflect the overall higher incidence of strabismus among premature and low-birth-weight infants.The overall incidence of strabismus and the incidence of specific types of strabismus show appreciable differences between racial groups, further supporting the relevance of genetic factors. Two studies have documented a lower incidence of all types of strabismus among Africans or African Americans (0.5% and 0.6%, respectively) relative to Americans of European ancestry (2.5%; refs. 5 and 6). Moreover, the majority of African, African American, and Asian strabismics are exotropes, whereas the majority of Caucasian strabismics are esotropes (5-7).With respect to overall heritability, the relative risk for first degree relatives of an affected individual is estimated to be between 3 and 5. Crone and Vezeboer (8) found that 13% of parents of strabismic probands had strabismus vs. a 3% incidence in the general population. Hu (9) found a 9% incidence among first-degree relatives and a 2.2% incidence among second degree relatives, versus ...