Duncan Laramie, Yilmaz Zeynep, Gaspar Helena, Walters Raymond, Goldstein Jackie, Anttila Verneri, Bulik-Sullivan Brendan, Ripke Stephan, Thornton Laura, Hinney Anke, Daly Mark, Sullivan Patrick F, Zeggini Eleftheria, Breen Gerome, Bulik Cynthia M
From the UNC Center of Excellence for Eating Disorders, Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, N.C.; the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; the Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston; the Social, Genetic, and Developmental Psychiatry Research Centre and Biomedical Research Centre for Mental Health at King's College London and South London and Maudsley NHS Trust; and the Broad Institute of MIT and Harvard, Cambridge, Mass.
Am J Psychiatry. 2017 Sep 1;174(9):850-858. doi: 10.1176/appi.ajp.2017.16121402. Epub 2017 May 12.
The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes.
Following uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h]), partitioned heritability, and genetic correlations (r) between anorexia nervosa and 159 other phenotypes.
Results were obtained for 10,641,224 SNPs and insertion-deletion variants with minor allele frequencies >1% and imputation quality scores >0.6. The h of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes.
Anorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.
作者开展了一项神经性厌食症的全基因组关联研究，并计算了与一系列精神、教育和代谢表型的遗传相关性。
在12个病例对照队列中，作者采用千人基因组计划（第3阶段）进行统一质量控制和填充程序，这些队列包括3495例神经性厌食症病例和10982例对照。作者进行了标准关联分析，随后进行跨队列的荟萃分析。连锁不平衡评分回归用于计算全基因组常见变异遗传力（基于单核苷酸多态性[SNP]的遗传力[h]）、遗传性划分以及神经性厌食症与其他159种表型之间的遗传相关性（r）。
获得了10641224个次要等位基因频率>1%且填充质量评分>0.6的SNP和插入缺失变异的结果。神经性厌食症的h为0.20（标准误=0.02），这表明基于双胞胎的遗传力中有很大一部分来自常见遗传变异。作者在12号染色体上一个包含先前报道的1型糖尿病和自身免疫性疾病位点的区域中，鉴定出一个全基因组显著位点（rs4622308）。在神经性厌食症与精神分裂症、神经质、教育程度和高密度脂蛋白胆固醇之间观察到显著的正遗传相关性，在神经性厌食症与体重指数、胰岛素、葡萄糖和脂质表型之间观察到显著的负遗传相关性。
神经性厌食症是一种复杂的可遗传表型，本研究首次发现了其全基因组显著位点。神经性厌食症与精神表型和代谢特征也存在大量且显著的遗传相关性。研究结果促使人们将这种常致命的疾病重新概念化为一种具有精神和代谢病因的疾病。
