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1.  Genetic Association of Recovery from Eating Disorders: The Role of GABA Receptor SNPs 
Neuropsychopharmacology  2011;36(11):2222-2232.
Follow-up studies of eating disorders (EDs) suggest outcomes ranging from recovery to chronic illness or death, but predictors of outcome have not been consistently identified. We tested 5151 single-nucleotide polymorphisms (SNPs) in approximately 350 candidate genes for association with recovery from ED in 1878 women. Initial analyses focused on a strictly defined discovery cohort of women who were over age 25 years, carried a lifetime diagnosis of an ED, and for whom data were available regarding the presence (n=361 ongoing symptoms in the past year, ie, ‘ill') or absence (n=115 no symptoms in the past year, ie, ‘recovered') of ED symptoms. An intronic SNP (rs17536211) in GABRG1 showed the strongest statistical evidence of association (p=4.63 × 10−6, false discovery rate (FDR)=0.021, odds ratio (OR)=0.46). We replicated these findings in a more liberally defined cohort of women age 25 years or younger (n=464 ill, n=107 recovered; p=0.0336, OR=0.68; combined sample p=4.57 × 10−6, FDR=0.0049, OR=0.55). Enrichment analyses revealed that GABA (γ-aminobutyric acid) SNPs were over-represented among SNPs associated at p<0.05 in both the discovery (Z=3.64, p=0.0003) and combined cohorts (Z=2.07, p=0.0388). In follow-up phenomic association analyses with a third independent cohort (n=154 ED cases, n=677 controls), rs17536211 was associated with trait anxiety (p=0.049), suggesting a possible mechanism through which this variant may influence ED outcome. These findings could provide new insights into the development of more effective interventions for the most treatment-resistant patients.
PMCID: PMC3176559  PMID: 21750581
GABA; anorexia nervosa; recovery from eating disorders; genetic association; single nucleotide polymorphisms; eating/metabolic disorders; GABA; eating/metabolic disorders; neurogenetics; biological psychiatry; genetic association; anorexia nervosa; recovery from eating disorders; single-nucleotide polymorphisms; phenomic association
2.  Linkage analysis of anorexia and bulimia nervosa cohorts using selected behavioral phenotypes as quantitative traits or covariates 
To increase the likelihood of finding genetic variation conferring liability to eating disorders, we measured over 100 attributes thought to be related to liability to eating disorders on affected individuals from multiplex families and two cohorts: one recruited through a proband with anorexia nervosa (AN; AN cohort); the other recruited through a proband with bulimia nervosa (BN; BN cohort). By a multilayer decision process based on expert evaluation and statistical analysis, six traits were selected for linkage analysis (1): obsessionality (OBS), age at menarche (MENAR) and anxiety (ANX) for quantitative trait locus (QTL) linkage analysis; and lifetime minimum Body Mass Index (BMI), concern over mistakes (CM) and food-related obsessions (OBF) for covariate-based linkage analysis. The BN cohort produced the largest linkage signals: for QTL linkage analysis, four suggestive signals: (for MENAR, at 10p13; for ANX, at 1q31.1, 4q35.2, and 8q13.1); for covariate-based linkage analyses, both significant and suggestive linkages (for BMI, one significant [4q21.1] and three suggestive [3p23, 10p13, 5p15.3]; for CM, two significant [16p13.3, 14q21.1] and three suggestive [4p15.33, 8q11.23, 10p11.21]; and for OBF, one significant [14q21.1] and five suggestive [4p16.1, 10p13.1, 8q11.23, 16p13.3, 18p11.31]). Results from the AN cohort were far less compelling: for QTL linkage analysis, two suggestive signals (for OBS at 6q21 and for ANX at 9p21.3); for covariate-based linkage analysis, five suggestive signals (for BMI at 4q13.1, for CM at 11p11.2 and 17q25.1, and for OBF at 17q25.1 and 15q26.2). Overlap between the two cohorts was minimal for substantial linkage signals.
PMCID: PMC2590774  PMID: 16152574
Complex disease; endophenotype; liability; mixture model; regression
3.  Selection of eating-disorder phenotypes for linkage analysis 
Vulnerability to anorexia nervosa (AN) and bulimia nervosa (BN) arise from the interplay of genetic and environmental factors. To explore the genetic contribution, we measured over 100 psychiatric, personality and temperament phenotypes of individuals with eating disorders from 154 multiplex families accessed through an AN proband (AN cohort) and 244 multiplex families accessed through a BN proband (BN cohort). To select a parsimonious subset of these attributes for linkage analysis, we subjected the variables to a multilayer decision process based on expert evaluation and statistical analysis. Criteria for trait choice included relevance to eating disorders pathology, published evidence for heritability, and results from our data. Based on these criteria, we chose six traits to analyze for linkage. Obsessionality, Age-at-Menarche, and a composite Anxiety measure displayed features of heritable quantitative traits, such as normal distribution and familial correlation, and thus appeared ideal for quantitative trait locus (QTL) linkage analysis. By contrast, some families showed highly concordant and extreme values for three variables — lifetime minimum Body Mass Index (lowest BMI attained during the course of illness), concern over mistakes, and food-related obsessions — whereas others did not. These distributions are consistent with a mixture of populations, and thus the variables were matched with covariate linkage analysis. Linkage results appear in a subsequent report. Our report lays out a systematic roadmap for utilizing a rich set of phenotypes for genetic analyses, including the selection of linkage methods paired to those phenotypes.
PMCID: PMC2560991  PMID: 16152575
Complex disease; endophenotype; liability; clinical judgment; covariate selection; mixture model; regression

Results 1-3 (3)