De novo deleterious variants that may alter the dopaminergic reward pathway are associated with anorexia nervosa
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ORIGINAL ARTICLE
De novo deleterious variants that may alter the dopaminergic reward pathway are associated with anorexia nervosa Thierry Bienvenu1 · Nicolas Lebrun1 · Julia Clarke2 · Philibert Duriez3 · Philip Gorwood1,3 · Nicolas Ramoz1 Received: 21 July 2019 / Accepted: 17 October 2019 © Springer Nature Switzerland AG 2019
Abstract Purpose Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. Up to now, four genome-wide association studies of AN have been conducted to date and identified only few significant loci. However, both previous studies focused on common variation and on rare exonic variants. Currently, de novo variants are one of the most significant risk factors for neurodevelopmental disorders and psychiatric disorders. Methods We analyzed by whole exome sequencing a cohort of nine female AN individuals and their parents (mother and father), and focused our analysis on de novo variants. Results Here, we found seven de novo missense variants in potential genes in nine studied AN patients. Four of these genes (CSMD1, CREB3, PTPRD and GAB1) belong to a same signaling pathway involving neuron differentiation and dopamine pathway. Conclusions This study provides a list of interesting genes such as CSDM1 and CREB3 that are candidates to be involved in the etiology of anorexia nervosa. Level of Evidence basic research. Keywords Anorexia nervosa · Exome · De novo variants · CREB3 · Reward pathway
Introduction Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. Family studies of AN have consistently shown that first-degree relatives of AN sufferers have an increased risk of AN, compared with relatives of unaffected individuals [1]. Twin studies have Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40519-019-00802-9) contains supplementary material, which is available to authorized users. * Thierry Bienvenu [email protected] 1
Institut de Psychiatrie et de Neurosciences de Paris, Inserm U1266, 102 rue de la Santé, 75014 Paris, France
2
Service de Psychiatrie de l’enfant et de l’adolescent, Hôpital Universitaire Robert Debré, Paris, France
3
CMME, Hôpital Sainte‑Anne, Université Paris-Descartes, Paris, France
estimated the heritability of AN at 56%, with the majority of remaining variance in liability attributed to non-shared environmental factors [2]. Up to now, four genome-wide association studies of AN have been conducted to date. The first focused on common variation and identified 11 suggestive variants. None reached genome-wide significance in the primary analysis, although one variant approached genome-wide significance in an associated secondary analysis [3]. The second study identified two suggestively associated variants [4], and the third study identified the first genome-wide significant locus for AN [5]. More rece
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