Increased Risk of Essential Tremor in First-Degree Relatives of Patients with Parkinson’s Disease Walter A. Rocca, MD, MPH, 1,2 * James H. Bower, MD, 2 J. Eric Ahlskog, PhD, MD, 2 Alexis Elbaz, MD, PhD, 1,3 Brandon R. Grossardt, MS, 4 Shannon K. McDonnell, MS, 4 Daniel J. Schaid, PhD, 4 and Demetrius M. Maraganore, MD 2 1 Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, USA 2 Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA 3 Institut National de la Sante et de la Recherche ´ Me ´dical, Inserm, U708, Paris, F-75013, France 4 Division of Biostatistics, Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, USA Abstract: We conducted a historical cohort study of 981 first- degree relatives of 162 patients with Parkinson’s disease (PD) and of 838 first-degree relatives of 147 controls representative of the population of Olmsted County, Minnesota. In addition, we studied 2,684 first-degree relatives of 411 patients with PD referred to the Mayo Clinic. Relatives were interviewed and screened for tremor either directly or through a proxy, and those who screened positive were examined or copies of their medical records were obtained to confirm the diagnosis of essential tremor (ET). We also obtained ET information from a medical records-linkage system (family study method). In the population-based sample, the risk of ET was significantly in- creased for relatives of patients with onset of PD  66 years (first tertile; hazard ratio [HR] = 2.24; 95% confidence interval [95% CI] = 1.26 –3.98; P = 0.006). In the referral-based sample, the risk of ET among relatives increased with younger onset of PD in patients (linear trend; P = 0.001), and was higher in relatives of PD patients with the tremor-predominant or mixed form when compared with relatives of patients with the akinetic-rigid form, and in men compared with women. These findings suggest that PD and ET may share familial susceptibility factors. © 2007 Movement Disorder Society Key words: Parkinson’s disease; essential tremor; familial aggregation; genetics; cohort study. The evidence for an increased risk of essential tremor (ET) among relatives of patients with Parkinson’s dis- ease (PD) remains limited and conflicting. 1-4 As part of the Mayo Clinic Family Study of Parkinson’s Disease, 5-8 we studied the risk of ET among relatives of patients with PD using the family study method, i.e., considering each relative separately. 5 PATIENTS AND METHODS Study Design The study included four cohorts of relatives: (1) first- degree relatives of patients with incident PD from Olmsted County, Minnesota; (2) first-degree relatives of controls free of PD, parkinsonism, or tremor from the same Olmsted County population; (3) first-degree relatives of patients with PD referred to the Mayo Clinic from a 120-mile radius centered in Rochester, Minnesota; and (4) first-degree rel- atives of patients with PD referred to the Mayo Clinic from a broader 5-state region (including the remainder of Min- nesota, Iowa, and Wisconsin, and North and South Dakota). Members of all four cohorts were followed through inter- views, direct examinations, and review of medical records to ascertain ET. Details about the overall study design were reported elsewhere. 5-8 Only the methods specific for ET are reported here. All aspects of the study involving subject contact were approved by the institutional review boards of the Mayo Clinic and Olmsted Medical Center. Patients examined as part of the study signed an informed consent form. Patients with PD and Controls The medical records-linkage system of the Rochester Epidemiology Project was used to identify all subjects *Correspondence to: Dr. Walter A. Rocca, Division of Epidemiol- ogy, Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: rocca@mayo.edu Received 5 March 2007; Revised 13 April 2007; Accepted 20 April 2007 Published online 1 June 2007 in Wiley InterScience (www. interscience.wiley.com). DOI: 10.1002/mds.21584 Movement Disorders Vol. 22, No. 11, 2007, pp. 1607–1614 © 2007 Movement Disorder Society 1607