Predicting Disease Onset from Mutation Status Using Proband and Relative Data with Applications to Huntington's Disease

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expansion of CAG repeats in the IT15 gene. The age-at-onset (AAO) of HD is inversely related to the CAG repeat length and the minimum length thought to cause HD is 36. Accurate estimation of the AAO distribution based on CAG repeat length is important for genetic counseling and the design of clinical trials. In the Cooperative Huntington's Observational Research Trial (COHORT) study, the CAG repeat length is known for the proband participants. However, whether a family member shares the huntingtin gene status (CAG expanded or not) with the proband is unknown. In this work, we use the expectation-maximization (EM) algorithm to handle the missing huntingtin gene information in first-degree family members in COHORT, assuming that a family member has the same CAG length as the proband if the family member carries a huntingtin gene mutation. We perform simulation studies to examine performance of the proposed method and apply the methods to analyze COHORT proband and family combined data. Our analyses reveal that the estimated cumulative risk of HD symptom onset obtained from the combined data is slightly lower than the risk estimated from the proband data alone. 1. Introduction Huntington’s disease (HD) is a severe, autosomal dominantly inherited neurodegenerative disorder that affects motor, cognitive, and psychiatric function and is uniformly fatal. HD is caused by the expansion of CAG trinucleotide repeats at the huntingtin gene (IT15) [1, 2]. Affected individuals typically begin to show motor signs around 30–50 years of age and typically die 15–20 years after the disease onset [3]. Despite identification of the causative gene, there is currently no treatment that modifies disease progression. One large genetic epidemiological study of HD, the Cooperative Huntington’s Observational Research Trial (COHORT), including 42 Huntington study group research centers in North America and Australia, was initiated in 2005 and concluded in 2011 [4–6]. Participants in COHORT (probands) underwent a clinical evaluation and DNA from whole blood was genotyped for the length of the CAG-repeat huntingtin mutation. Since 2005, COHORT probands from sites with IRB approval have participated in family history interviews and have provided information on HD affection status in their family members. While CAG repeat length is ascertained in probands, the high cost of conducting in-person interviews of family members prevents the collection of all family members’ blood samples. However, family