Potential role of an additive genetic component in the cause of amyotrophic lateral sclerosis and parkinsonism-dementia in the western Pacific.

Amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia (PD) are neurological degenerative disorders that occur in three high incidence foci in the western Pacific: among the Chamorros of Guam and the Commonwealth of the Northern Marianas Islands, among Japanese on the Kii peninsula of Honshu Island, and among the Auyu and Jakai peoples of southern West New Guinea. Previous studies have implicated both genetic susceptibility and environmental risk factors in the causation and familial clustering of these disorders. The data analyzed consist of 2,026 individuals in nuclear families ascertained on Guam through two mechanisms: (1) nuclear families were included in the study if one or both parents in the family were affected with ALS or PD or both; and (2) a group of "controls" was selected by obtaining nuclear families where neither parent was affected and both had lived through the age of risk. Clinically, ALS and PD are two distinct disorders. However, preliminary analyses indicated that combining all three diagnoses into one affected diagnosis for genetic analyses (thereby assuming any genetic effect on susceptibility to the two disorders was due to the same genetic mechanism) was reasonable. An age, sex and birth cohort-specific liability was defined and segregation analysis was performed under both logistic and normal models for this liability at the time of disease onset. Under either model, purely environmental, Mendelian dominant and Mendelian recessive hypotheses could be rejected, but a two-allele additive major locus hypothesis could not be rejected.