METHODS: Whole-exome sequencing (WES) was carried out on a 15-year-old male proband of Pakistani ancestry who had severe obesity. This was followed by family segregation analysis, using Sanger sequencing. We also undertook re-analysis of WES data from 91 unrelated adults with severe obesity (86% white European ancestry) from the Personalised Medicine for Morbid Obesity (PMMO) cohort, recruited from the UK National Health Service.

RESULTS: We identified an oligogenic mode of inheritance of obesity in the proband's family-this provided the impetus to reanalyze existing sequence data in a separate dataset. Analysis of PMMO participant data revealed two further patients who carried more than one rare, predicted-deleterious mutation in a known monogenic obesity gene. In all three cases, the genes involved had known autosomal dominant inheritance, with incomplete penetrance.

METHODS: The study included individuals from the Northern Finland Birth Cohort 1966 (NFBC1966) who had available data for adiposity measures (body mass index and waist-to-hip ratio), alexithymia (measured by the 20-Item Toronto Alexithymia Scale: TAS-20), depressive symptoms (measured by the 13-item depression subscale of Hopkins Symptom Checklist: HSCL-13) at age of 31 years (n = 4773) and 46 years (n = 4431). Pearson's (r) correlation, and multiple linear regression were used to investigate the relationships between alexithymia, depressive symptoms, and adiposity measures. The potential mediating role of depressive symptoms was examined via Hayes' procedure (PROCESS).