Psychiatric disorders in <i>C9orf72</i> kindreds: Study of 1,414 family members.

Abstract

The aim of this study was to determine in a systematic manner if the <i>C9orf72</i> phenotype might extend beyond frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) to include psychiatric disease. A validated semistructured family history interview was conducted in a large cohort of patients with FTD and ALS (n = 89), with and without the <i>C9orf72</i> expansion (n = 29 and n = 60, respectively), encompassing 1,414 first- and second-degree relatives. Statistical analyses used both the hazard ratio (HR) and the relative risk ratio to determine the risk profiles within families. A significant HR of 4.9 (95% confidence interval [CI]: 1.9-13.9, <i>p</i> = 0.003) confirmed a higher probability of developing schizophrenia for relatives of <i>C9orf72</i> carriers compared with noncarriers. In addition, 8 relatives of <i>C9orf72</i> carriers experienced an episode of late-onset psychosis unrelated to schizophrenia, in comparison to one noncarrier (HR = 17.9, 95% CI: 2.2-143.2, <i>p</i> = 0.007). The probability of suicide was also significantly higher for family members of <i>C9orf72</i> carriers (HR = 2.7, 95% CI: 1.2-6.2, <i>p</i> = 0.02). An HR of 2.7 (95% CI: 1.1-6.9, <i>p</i> = 0.03) indicated a higher probability of autism spectrum disorder (ASD) in family members of <i>C9orf72</i> carriers, and this risk extended to FTD. Furthermore, there was a positive association between psychosis in probands and mental health disorders, including ASD in their family members (<i>p</i> = 0.04). Overall, the results from this study suggest that a psychiatric phenotype exists within <i>C9orf72</i> kindreds. Further studies should attempt to delineate the risk of psychiatric disorders in <i>C9orf72</i> kindreds to aid in clinical decision making, particularly regarding genetic counseling, through collaborations between neurology and psychiatry.