RESUMEN
Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.
Asunto(s)
Trastorno Autístico/genética , Mapeo Cromosómico/métodos , Cromosomas Humanos Par 16/fisiología , Obesidad/genética , Adolescente , Adulto , Anciano , Trastorno del Espectro Autista/genética , Índice de Masa Corporal , Niño , Preescolar , Cromatina/metabolismo , Cromatina/fisiología , Deleción Cromosómica , Duplicación Cromosómica , Cromosomas Humanos Par 16/genética , Variaciones en el Número de Copia de ADN/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Discapacidad Intelectual/genética , Masculino , Megalencefalia/genética , Microcefalia/genética , Persona de Mediana Edad , FenotipoRESUMEN
BACKGROUND: The 600 kb BP4-BP5 copy number variants (CNVs) at the 16p11.2 locus have been associated with a range of neurodevelopmental conditions including autism spectrum disorders and schizophrenia. The number of genomic copies in this region is inversely correlated with body mass index (BMI): the deletion is associated with a highly penetrant form of obesity (present in 50% of carriers by the age of 7 years and in 70% of adults), and the duplication with being underweight. Mechanisms underlying this energy imbalance remain unknown. OBJECTIVE: This study aims to investigate eating behavior, cognitive traits and their relationships with BMI in carriers of 16p11.2 CNVs. METHODS: We assessed individuals carrying a 16p11.2 deletion or duplication and their intrafamilial controls using food-related behavior questionnaires and cognitive measures. We also compared these carriers with cohorts of individuals presenting with obesity, binge eating disorder or bulimia. RESULTS: Response to satiety is gene dosage-dependent in pediatric CNV carriers. Altered satiety response is present in young deletion carriers before the onset of obesity. It remains altered in adolescent carriers and correlates with obesity. Adult deletion carriers exhibit eating behavior similar to that seen in a cohort of obesity without eating disorders such as bulimia or binge eating. None of the cognitive measures are associated with eating behavior or BMI. CONCLUSIONS: These findings suggest that abnormal satiety response is a strong contributor to the energy imbalance in 16p11.2 CNV carriers, and, akin to other genetic forms of obesity, altered satiety responsiveness in children precedes the increase in BMI observed later in adolescence.
Asunto(s)
Trastorno Autístico/genética , Trastorno Autístico/fisiopatología , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/fisiopatología , Cromosomas Humanos Par 16/genética , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Obesidad/genética , Saciedad , Adulto , Trastorno Autístico/complicaciones , Índice de Masa Corporal , Estudios de Casos y Controles , Niño , Deleción Cromosómica , Trastornos de los Cromosomas/complicaciones , Disfunción Cognitiva/etiología , Disfunción Cognitiva/genética , Disfunción Cognitiva/fisiopatología , Variaciones en el Número de Copia de ADN/genética , Metabolismo Energético/genética , Metabolismo Energético/fisiología , Función Ejecutiva , Conducta Alimentaria/fisiología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Discapacidad Intelectual/complicaciones , Masculino , Obesidad/etiología , Obesidad/fisiopatología , Fenotipo , Eliminación de Secuencia/genética , SuizaRESUMEN
Anatomical structures and mechanisms linking genes to neuropsychiatric disorders are not deciphered. Reciprocal copy number variants at the 16p11.2 BP4-BP5 locus offer a unique opportunity to study the intermediate phenotypes in carriers at high risk for autism spectrum disorder (ASD) or schizophrenia (SZ). We investigated the variation in brain anatomy in 16p11.2 deletion and duplication carriers. Beyond gene dosage effects on global brain metrics, we show that the number of genomic copies negatively correlated to the gray matter volume and white matter tissue properties in cortico-subcortical regions implicated in reward, language and social cognition. Despite the near absence of ASD or SZ diagnoses in our 16p11.2 cohort, the pattern of brain anatomy changes in carriers spatially overlaps with the well-established structural abnormalities in ASD and SZ. Using measures of peripheral mRNA levels, we confirm our genomic copy number findings. This combined molecular, neuroimaging and clinical approach, applied to larger datasets, will help interpret the relative contributions of genes to neuropsychiatric conditions by measuring their effect on local brain anatomy.
Asunto(s)
Trastorno Autístico/genética , Encéfalo/patología , Cromosomas Humanos Par 16/genética , Variaciones en el Número de Copia de ADN/genética , Obesidad/genética , Esquizofrenia/genética , Adolescente , Adulto , Antropometría , Proteínas de Arabidopsis/metabolismo , Trastorno Autístico/patología , Índice de Masa Corporal , Mapeo Encefálico , Niño , Femenino , Dosificación de Gen , Estudios de Asociación Genética , Humanos , Transferasas Intramoleculares/metabolismo , Masculino , Persona de Mediana Edad , Obesidad/patología , Fenotipo , Escalas de Valoración Psiquiátrica , Esquizofrenia/patología , Adulto JovenRESUMEN
Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.
Asunto(s)
Anorexia Nerviosa/genética , Pueblo Asiatico/genética , Calcineurina/genética , Proteínas Portadoras/genética , Estudios de Casos y Controles , Proteínas Cullin/genética , Femenino , Estudio de Asociación del Genoma Completo , Factores de Intercambio de Guanina Nucleótido/genética , Humanos , Japón , Masculino , Metaanálisis como Asunto , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple , Población Blanca/genéticaRESUMEN
We report on a de novo 17q21.33 microdeletion, 1.8 Mb in size, detected in a patient with mild intellectual disability, growth retardation, poor weight gain, microcephaly, long face, large beaked nose, thick lower lip, micrognathia and other dysmorphic features. The deletion was detected by whole-genome genotyping BeadChip assay and involves the genomic region between 45,682,246 and 47,544,816 bp on chromosome 17. Among the 24 RefSeq genes included in this deletion are the CA10 and CACNA1G genes that are involved in brain development and neurological processes. A possible candidate gene for the prenatal and postnatal growth retardation is the CHAD gene, which product chondroadherin is a cartilage protein with cell binding properties. These three genes may be responsible for the patient's phenotype.
