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1.  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.
doi:10.1002/ajmg.b.30226
PMCID: PMC2590774  PMID: 16152574
Complex disease; endophenotype; liability; mixture model; regression
2.  Anorexia nervosa trios: behavioral profiles of individuals with anorexianervosa and their parents 
Psychological medicine  2008;39(3):451-461.
Background
Anorexia nervosa (AN) is associated with behavioral traits that predate the onset of AN and persist after recovery. We identified patterns of behavioral traits in AN trios (proband plus two biological parents).
Method
A total of 433 complete trios were collected in the Price Foundation Genetic Study of AN using standardized instruments for eating disorder (ED) symptoms, anxiety, perfectionism, and temperament. We used latent profile analysis and ANOVA to identify and validate patterns of behavioral traits.
Results
We distinguished three classes with medium to large effect sizes by mothers’ and probands’ drive for thinness, body dissatisfaction, perfectionism, neuroticism, trait anxiety, and harm avoidance. Fathers did not differ significantly across classes. Classes were distinguished by degree of symptomatology rather than qualitative differences. Class 1 (~33 %) comprised low symptom probands and mothers with scores in the healthy range. Class 2 (~43 %) included probands with marked elevations in drive for thinness, body dissatisfaction, neuroticism, trait anxiety, and harm avoidance and mothers with mild anxious/perfectionistic traits. Class 3 (~24 %) included probands and mothers with elevations on ED and anxious/perfectionistic traits. Mother–daughter symptom severity was related in classes 1 and 3 only. Trio profiles did not differ significantly by proband clinical status or subtype.
Conclusions
A key finding is the importance of mother and daughter traits in the identification of temperament and personality patterns in families affected by AN. Mother–daughter pairs with severe ED and anxious/perfectionistic traits may represent a more homogeneous and familial variant of AN that could be of value in genetic studies.
doi:10.1017/S0033291708003826
PMCID: PMC3714180  PMID: 18578898
Anorexia nervosa; eating disorder; genetics; temperament
3.  The Genetics of Anorexia Nervosa Collaborative Study: Methods and Sample Description 
Objective
Supported by National Institute of Mental Health (NIMH), this 12-site international collaboration seeks to identify genetic variants that affect risk for anorexia nervosa (AN).
Method
Four hundred families will be ascertained with two or more individuals affected with AN. The assessment battery produces a rich set of phenotypes comprising eating disorder diagnoses and psychological and personality features known to be associated with vulnerability to eating disorders.
Results
We report attributes of the first 200 families, comprising 200 probands and 232 affected relatives.
Conclusion
These results provide context for the genotyping of the first 200 families by the Center for Inherited Disease Research. We will analyze our first 200 families for linkage, complete recruitment of roughly 400 families, and then perform final linkage analyses on the complete cohort. DNA, genotypes, and phenotypes will form a national eating disorder repository maintained by NIMH and available to qualified investigators.
doi:10.1002/eat.20509
PMCID: PMC3755506  PMID: 18236451
anorexia nervosa; eating disorders; bulimia nervosa; psychiatric disorders; genetics; linkage analysis; genomics
4.  Psychological and weight-related characteristics of patients with anorexia nervosa-restricting type who later develop bulimia nervosa 
Background
Patients with anorexia nervosa-restricting type (AN-R) sometimes develop accompanying bulimic symptoms or the full syndrome of bulimia nervosa (BN). If clinicians could predict who might change into the bulimic sub-type or BN, preventative steps could be taken. Therefore, we investigated anthropometric and psychological factors possibly associated with such changes.
Method
All participants were from a study by the Japanese Genetic Research Group for Eating Disorders. Of 80 patients initially diagnosed with AN-R, 22 changed to the AN-Binge Eating/Purging Type (AN-BP) and 14 to BN for some period of time. The remaining 44 patients remained AN-R only from the onset to the investigation period. Variables compared by ANOVA included anthropometric measures, personality traits such as Multiple Perfectionism Scale scores and Temperament and Character Inventory scores, and Beck Depression Inventory-II scores.
Results
In comparison with AN-R only patients, those who developed BN had significantly higher current BMI (p < 0.05) and maximum BMI in the past (p < 0.05). They also scored significantly higher for the psychological characteristic of parental criticism (p < 0.05) and lower in self-directedness (p < 0.05), which confirms previous reports, but these differences disappeared when the depression score was used as a co-variant. No significant differences were obtained for personality traits or depression among the AN-R only patients irrespective of their duration of illness.
Conclusion
The present findings suggest a tendency toward obesity among patients who cross over from AN-R to BN. Low self-directedness and high parental criticism may be associated with the development of BN by patients with AN-R, although the differences may also be associated with depression.
doi:10.1186/1751-0759-2-5
PMCID: PMC2275291  PMID: 18267038
5.  A twin study of specific bulimia nervosa symptoms 
Psychological medicine  2009;40(7):1203-1213.
Background
Twin studies have suggested that additive genetic factors significantly contribute to liability to bulimia nervosa (BN). However, the diagnostic criteria for BN remain controversial. In this study, an item-factor model was used to examine the BN diagnostic criteria and the genetic and environmental contributions to BN in a population-based twin sample. The validity of the equal environment assumption (EEA) for BN was also tested.
Method
Participants were 1024 female twins (MZ n=614, DZ n=410) from the population-based Mid-Atlantic Twin Registry. BN was assessed using symptom-level (self-report) items consistent with DSM-IV and ICD-10 diagnostic criteria. Items assessing BN were included in an item-factor model. The EEA was measured by items assessing similarity of childhood and adolescent environment, which have demonstrated construct validity. Scores on the EEA factor were used to specify the degree to which twins shared environmental experiences in this model.
Results
The EEA was not violated for BN. Modeling results indicated that the majority of the variance in BN was due to additive genetic factors. There was substantial variability in additive genetic and environmental contributions to specific BN symptoms. Most notably, vomiting was very strongly influenced by additive genetic factors, while other symptoms were much less heritable, including the influence of weight on self-evaluation. These results highlight the importance of assessing eating disorders at the symptom level.
Conclusions
Refinement of eating disorder phenotypes could ultimately lead to improvements in treatment and targeted prevention, by clarifying sources of variation for specific components of symptomatology.
doi:10.1017/S003329170999122X
PMCID: PMC2882507  PMID: 19818201
Bulimia nervosa; heritability; item-factor model; twins
6.  Novel quantitative trait locus is mapped to chromosome 12p11 for left ventricular mass in Dominican families: the Family Study of Stroke Risk and Carotid Atherosclerosis 
BMC Medical Genetics  2009;10:74.
Background
Left ventricular mass (LVM) is an important risk factor for stroke and vascular disease. The genetic basis of LVM is unclear although a high heritability has been suggested. We sought to map quantitative trait loci (QTL) for LVM using large Dominican families.
Methods
Probands were selected from Dominican subjects of the population-based Northern Manhattan Study (NOMAS). LVM was measured by transthoracic echocardiography. A set of 405 microsatellite markers was used to screen the whole genome among 1360 subjects from 100 Dominican families who had complete phenotype data and DNA available. A polygenic covariate screening was run to identify the significant covariates. Variance components analysis was used to estimate heritability and to detect evidence for linkage, after adjusting for significant risk factors. Ordered-subset Analysis (OSA) was conducted to identify a more homogeneous subset for stratification analysis.
Results
LVM had a heritability of 0.58 in the studied population (p < 0.0001). The most significant evidence for linkage was found at chromosome 12p11 (MLOD = 3.11, empirical p = 0.0003) with peak marker at D12S1042. This linkage was significantly increased in a subset of families with the high average waist circumference (MLOD = 4.45, p = 0.0045 for increase in evidence for linkage).
Conclusion
We mapped a novel QTL near D12S1042 for LVM in Dominicans. Enhanced linkage evidence in families with larger waist circumference suggests that gene(s) residing within the QTL interact(s) with abdominal obesity to contribute to phenotypic variation of LVM. Suggestive evidence for linkage (LOD = 1.99) has been reported at the same peak marker for left ventricular geometry in a White population from the HyperGEN study, underscoring the importance of this QTL for left ventricular phenotype. Further fine mapping and validation studies are warranted to identify the underpinning genes.
doi:10.1186/1471-2350-10-74
PMCID: PMC2724377  PMID: 19627612
7.  Novel genomic approaches unravel genetic architecture of complex traits in apple 
BMC Genomics  2013;14:393.
Background
Understanding the genetic architecture of quantitative traits is important for developing genome-based crop improvement methods. Genome-wide association study (GWAS) is a powerful technique for mining novel functional variants. Using a family-based design involving 1,200 apple (Malus × domestica Borkh.) seedlings genotyped for an 8K SNP array, we report the first systematic evaluation of the relative contributions of different genomic regions to various traits related to eating quality and susceptibility to some physiological disorders. Single-SNP analyses models that accounted for population structure, or not, were compared with models fitting all markers simultaneously. The patterns of linkage disequilibrium (LD) were also investigated.
Results
A high degree of LD even at longer distances between markers was observed, and the patterns of LD decay were similar across successive generations. Genomic regions were identified, some of which coincided with known candidate genes, with significant effects on various traits. Phenotypic variation explained by the loci identified through a whole-genome scan ranged from 3% to 25% across different traits, while fitting all markers simultaneously generally provided heritability estimates close to those from pedigree-based analysis. Results from ‘Q+K’ and ‘K’ models were very similar, suggesting that the SNP-based kinship matrix captures most of the underlying population structure. Correlations between allele substitution effects obtained from single-marker and all-marker analyses were about 0.90 for all traits. Use of SNP-derived realized relationships in linear mixed models provided a better goodness-of-fit than pedigree-based expected relationships. Genomic regions with probable pleiotropic effects were supported by the corresponding higher linkage group (LG) level estimated genetic correlations.
Conclusions
The accuracy of artificial selection in plants species can be increased by using more precise marker-derived estimates of realized coefficients of relationships. All-marker analyses that indirectly account for population- and pedigree structure will be a credible alternative to single-SNP analyses in GWAS. This study revealed large differences in the genetic architecture of apple fruit traits, and the marker-trait associations identified here will help develop genome-based breeding methods for apple cultivar development.
doi:10.1186/1471-2164-14-393
PMCID: PMC3686700  PMID: 23758946
GWAS; Linkage disequilibrium; Genetic architecture; Allele substitution effect; Pleiotropy; Malus × domestica
8.  Genome-Wide Association Analysis of Eating Disorder-Related Symptoms, Behaviors, and Personality Traits 
American Journal of Medical Genetics  2012;159B(7):803-811.
Eating disorders (EDs) are common, complex psychiatric disorders thought to be caused by both genetic and environmental factors. They share many symptoms, behaviors, and personality traits, which may have overlapping heritability. The aim of the present study is to perform a genome-wide association scan (GWAS) of six ED phenotypes comprising three symptom traits from the Eating Disorders Inventory 2 [Drive for Thinness (DT), Body Dissatisfaction (BD), and Bulimia], Weight Fluctuation symptom, Breakfast Skipping behavior and Childhood Obsessive-Compulsive Personality Disorder trait (CHIRP). Investigated traits were derived from standardized self-report questionnaires completed by the TwinsUK population-based cohort. We tested 283,744 directly typed SNPs across six phenotypes of interest in the TwinsUK discovery dataset and followed-up signals from various strata using a two-stage replication strategy in two independent cohorts of European ancestry. We meta-analyzed a total of 2,698 individuals for DT, 2,680 for BD, 2,789 (821 cases/1,968 controls) for Bulimia, 1,360 (633 cases/727 controls) for Childhood Obsessive-Compulsive Personality Disorder trait, 2,773 (761 cases/2,012 controls) for Breakfast Skipping, and 2,967 (798 cases/2,169 controls) for Weight Fluctuation symptom. In this GWAS analysis of six ED-related phenotypes, we detected association of eight genetic variants with P < 10−5. Genetic variants that showed suggestive evidence of association were previously associated with several psychiatric disorders and ED-related phenotypes. Our study indicates that larger-scale collaborative studies will be needed to achieve the necessary power to detect loci underlying ED-related traits. © 2012 Wiley Periodicals, Inc.
doi:10.1002/ajmg.b.32087
PMCID: PMC3494378  PMID: 22911880
Drive for Thinness; Body Dissatisfaction; Childhood Obsessive Compulsive Personality Disorder; Weight Fluctuation; Breakfast Skipping
9.  Assessing the Heritability of Anorexia Nervosa Symptoms Using a Marginal Maximal Likelihood Approach 
Psychological medicine  2008;39(3):463-473.
Background
Assessment of eating disorders at the symptom level can facilitate the refinement of phenotypes. We examined genetic and environmental contributions to liability to anorexia nervosa (AN) symptoms in a population-based twin sample using a genetic common pathway model.
Method
Participants were from the Norwegian Institute of Public Health Twin Panel and included all female monozygotic (n = 448 complete pairs and 4 singletons) and dizygotic (n = 263 complete pairs and 4 singletons) twins who completed the Composite International Diagnostic Interview assessing DSM-IV axis I and ICD-10 criteria. Responses to items assessing AN symptoms were included in a model fitted using marginal maximum likelihood.
Results
Heritability of the overall AN diagnosis was moderate (a2 = .22, 95% CI: 0.0; .50), whereas heritabilities of the specific items varied. Heritability estimates for weight loss items were moderate (a2 estimates ranged from .31 to .34) and items assessing weight concern when at a low weight were smaller (ranging from .18 to .29). Additive genetic factors contributed little to the variance of amenorrhea, which was most strongly influenced by unshared environment (a2 =.16; e2 = .71).
Conclusions
AN symptoms are differentially heritable. Specific criteria such as those related to body weight and weight loss history represent more biologically driven potential endophenotypes or liability indices. Results regarding weight concern differ somewhat from those of previous studies, which highlights the importance of assessing genetic and environmental influences on variance of traits within specific subgroups of interest.
doi:10.1017/S0033291708003310
PMCID: PMC2640444  PMID: 18485259
10.  Replication of linkage at chromosome 20p13 and identification of suggestive sex-differential risk loci for autism spectrum disorder 
Molecular Autism  2014;5:13.
Background
Autism spectrum disorders (ASDs) are male-biased and genetically heterogeneous. While sequencing of sporadic cases has identified de novo risk variants, the heritable genetic contribution and mechanisms driving the male bias are less understood. Here, we aimed to identify familial and sex-differential risk loci in the largest available, uniformly ascertained, densely genotyped sample of multiplex ASD families from the Autism Genetics Resource Exchange (AGRE), and to compare results with earlier findings from AGRE.
Methods
From a total sample of 1,008 multiplex families, we performed genome-wide, non-parametric linkage analysis in a discovery sample of 847 families, and separately on subsets of families with only male, affected children (male-only, MO) or with at least one female, affected child (female-containing, FC). Loci showing evidence for suggestive linkage (logarithm of odds ≥2.2) in this discovery sample, or in previous AGRE samples, were re-evaluated in an extension study utilizing all 1,008 available families. For regions with genome-wide significant linkage signal in the discovery stage, those families not included in the corresponding discovery sample were then evaluated for independent replication of linkage. Association testing of common single nucleotide polymorphisms (SNPs) was also performed within suggestive linkage regions.
Results
We observed an independent replication of previously observed linkage at chromosome 20p13 (P < 0.01), while loci at 6q27 and 8q13.2 showed suggestive linkage in our extended sample. Suggestive sex-differential linkage was observed at 1p31.3 (MO), 8p21.2 (FC), and 8p12 (FC) in our discovery sample, and the MO signal at 1p31.3 was supported in our expanded sample. No sex-differential signals met replication criteria, and no common SNPs were significantly associated with ASD within any identified linkage regions.
Conclusions
With few exceptions, analyses of subsets of families from the AGRE cohort identify different risk loci, consistent with extreme locus heterogeneity in ASD. Large samples appear to yield more consistent results, and sex-stratified analyses facilitate the identification of sex-differential risk loci, suggesting that linkage analyses in large cohorts are useful for identifying heritable risk loci. Additional work, such as targeted re-sequencing, is needed to identify the specific variants within these loci that are responsible for increasing ASD risk.
doi:10.1186/2040-2392-5-13
PMCID: PMC3942516  PMID: 24533643
Male brain; Sex differences; Intermediate phenotype; Linkage analysis; Association; AGRE
11.  An examination of autism spectrum traits in adolescents with anorexia nervosa and their parents 
Molecular Autism  2014;5(1):56.
Background
There may be a link between anorexia nervosa and autism spectrum disorders. The aims of this study were to examine whether adolescents with anorexia nervosa have autism spectrum and/or obsessive-compulsive traits, how many would meet diagnostic criteria for autism spectrum disorder, and whether these traits are shared by parents.
Methods
A total of 150 adolescents receiving outpatient treatment for anorexia nervosa or subthreshold anorexia nervosa and their parents completed the autism spectrum disorder and eating disorder sections of the Development and Well-being Assessment. Patients also completed the Children Yale-Brown Obsessive-Compulsive Scale and other measures of psychiatric morbidity, and parents completed the short Autism Quotient and Obsessive-Compulsive Inventory Revised.
Results
Adolescents with anorexia nervosa had a below average social aptitude (19% below cut-off) and high levels of peer relationship problems (39% above cut-off) and obsessive-compulsive symptoms (56% above cut-off). Six cases (4%, all females) were assigned a possible (n = 5) or definite (n = 1) diagnosis of autism spectrum disorder. Parental levels of autism spectrum and obsessive-compulsive traits were within the normal range.
Conclusions
This study suggests that adolescents with anorexia nervosa have elevated levels of autism spectrum traits, obsessive-compulsive symptoms, and a small proportion fulfil diagnostic criteria for a probable autism spectrum disorder. These traits did not appear to be familial. This comorbidity has been associated with a poorer prognosis. Therefore, adaptation of treatment for this subgroup may be warranted.
Trial registration
Controlled-trials.com: ISRCTN83003225. Registered on 29 September 2011.
doi:10.1186/2040-2392-5-56
PMCID: PMC4280745  PMID: 25553237
Anorexia nervosa; Eating disorder; Autism spectrum disorder; Obsessive-compulsive disorder; Traits; Social aptitude; Adolescents; Parents; Development; Well-being assessment
12.  A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study 
BMC Medical Genetics  2007;8(Suppl 1):S17.
Background
Blood lipid levels including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are highly heritable. Genome-wide association is a promising approach to map genetic loci related to these heritable phenotypes.
Methods
In 1087 Framingham Heart Study Offspring cohort participants (mean age 47 years, 52% women), we conducted genome-wide analyses (Affymetrix 100K GeneChip) for fasting blood lipid traits. Total cholesterol, HDL-C, and TG were measured by standard enzymatic methods and LDL-C was calculated using the Friedewald formula. The long-term averages of up to seven measurements of LDL-C, HDL-C, and TG over a ~30 year span were the primary phenotypes. We used generalized estimating equations (GEE), family-based association tests (FBAT) and variance components linkage to investigate the relationships between SNPs (on autosomes, with minor allele frequency ≥10%, genotypic call rate ≥80%, and Hardy-Weinberg equilibrium p ≥ 0.001) and multivariable-adjusted residuals. We pursued a three-stage replication strategy of the GEE association results with 287 SNPs (P < 0.001 in Stage I) tested in Stage II (n ~1450 individuals) and 40 SNPs (P < 0.001 in joint analysis of Stages I and II) tested in Stage III (n~6650 individuals).
Results
Long-term averages of LDL-C, HDL-C, and TG were highly heritable (h2 = 0.66, 0.69, 0.58, respectively; each P < 0.0001). Of 70,987 tests for each of the phenotypes, two SNPs had p < 10-5 in GEE results for LDL-C, four for HDL-C, and one for TG. For each multivariable-adjusted phenotype, the number of SNPs with association p < 10-4 ranged from 13 to 18 and with p < 10-3, from 94 to 149. Some results confirmed previously reported associations with candidate genes including variation in the lipoprotein lipase gene (LPL) and HDL-C and TG (rs7007797; P = 0.0005 for HDL-C and 0.002 for TG). The full set of GEE, FBAT and linkage results are posted at the database of Genotype and Phenotype (dbGaP). After three stages of replication, there was no convincing statistical evidence for association (i.e., combined P < 10-5 across all three stages) between any of the tested SNPs and lipid phenotypes.
Conclusion
Using a 100K genome-wide scan, we have generated a set of putative associations for common sequence variants and lipid phenotypes. Validation of selected hypotheses in additional samples did not identify any new loci underlying variability in blood lipids. Lack of replication may be due to inadequate statistical power to detect modest quantitative trait locus effects (i.e., <1% of trait variance explained) or reduced genomic coverage of the 100K array. GWAS in FHS using a denser genome-wide genotyping platform and a better-powered replication strategy may identify novel loci underlying blood lipids.
doi:10.1186/1471-2350-8-S1-S17
PMCID: PMC1995614  PMID: 17903299
13.  Exploring pleiotropy using principal components 
BMC Genetics  2003;4(Suppl 1):S53.
A standard multivariate principal components (PCs) method was utilized to identify clusters of variables that may be controlled by a common gene or genes (pleiotropy). Heritability estimates were obtained and linkage analyses performed on six individual traits (total cholesterol (Chol), high and low density lipoproteins, triglycerides (TG), body mass index (BMI), and systolic blood pressure (SBP)) and on each PC to compare our ability to identify major gene effects. Using the simulated data from Genetic Analysis Workshop 13 (Cohort 1 and 2 data for year 11), the quantitative traits were first adjusted for age, sex, and smoking (cigarettes per day). Adjusted variables were standardized and PCs calculated followed by orthogonal transformation (varimax rotation). Rotated PCs were then subjected to heritability and quantitative multipoint linkage analysis. The first three PCs explained 73% of the total phenotypic variance. Heritability estimates were above 0.60 for all three PCs. We performed linkage analyses on the PCs as well as the individual traits. The majority of pleiotropic and trait-specific genes were not identified. Standard PCs analysis methods did not facilitate the identification of pleiotropic genes affecting the six traits examined in the simulated data set. In addition, genes contributing 20% of the variance in traits with over 0.60 heritability estimates could not be identified in this simulated data set using traditional quantitative trait linkage analyses. Lack of identification of pleiotropic and trait-specific genes in some cases may reflect their low contribution to the traits/PCs examined or more importantly, characteristics of the sample group analyzed, and not simply a failure of the PC approach itself.
doi:10.1186/1471-2156-4-S1-S53
PMCID: PMC1866490  PMID: 14975121
multivariate analysis; principle components; quantitative traits; heritability estimates; linkage
14.  Anorexia nervosa 
Clinical Evidence  2009;2009:1011.
Introduction
Anorexia nervosa is characterised by a low body mass index (BMI), fear of gaining weight, denial of current low weight and its impact on health, and amenorrhoea. Estimated prevalence is highest in teenage girls, and up to 0.7% of this age group may be affected. While most people with anorexia nervosa recover completely or partially, about 5% die of the condition, and 20% develop a chronic eating disorder. Young women with anorexia nervosa are at increased risk of bone fractures later in life.
Methods and outcomes
We conducted a systematic review which aimed to answer the following clinical questions: What are the effects of treatments for anorexia nervosa? What are the effects of interventions to prevent or treat complications of anorexia nervosa? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 40 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: anxiolytic drugs, cyproheptadine, inpatient/outpatient treatment setting, oestrogen treatment, psychotherapy, refeeding, selective serotonin reuptake inhibitors (SSRIs), and tricyclic antidepressants.
Key Points
Anorexia nervosa is characterised by a low BMI, fear of gaining weight, denial of current low weight and its impact on health, and amenorrhoea. Estimated prevalence is highest in teenage girls, and may affect up to 0.7% of this group.Anorexia nervosa is related to family, sociocultural, genetic, and other biological factors. Psychiatric and personality disorders such as depression, anxiety disorders, obsessive compulsive disorder, and perfectionism, are commonly found in people who have anorexia nervosa.Most people with anorexia nervosa recover completely or partially, but about 5% die from the condition and 20% develop a chronic eating disorder.Young women with anorexia nervosa are at increased risk of fractures later in life.
There is no strong research evidence that any treatments work well for anorexia nervosa. However, there is a gradual accumulation of evidence which suggests that early intervention is effective. Working with the family may also interrupt the development of a persistent form of the illness.
Evidence on the benefits of psychotherapy is unclear.
Refeeding is a necessary and effective component of treatment, but is not sufficient alone. Very limited evidence from a quasi-experimental study suggests that a lenient approach to refeeding is as effective and more acceptable compared with a more strict approach.Refeeding may be as effective in an outpatient setting as during hospital admission.Nasogastric feeding is rarely required and can lead to problems due to hypophosphataemia.Nutritional supplements, including zinc, have only limited evidence for their effectiveness, and additional evaluation of these measures are warranted.
Limited evidence from small RCTs has not shown significant weight gain from SSRIs or tricyclic antidepressants, some of which may cause serious adverse effects. Tricyclic antidepressants may cause drowsiness, dry mouth, blurred vision, and a prolonged QT interval in people who have anorexia nervosa. SSRIs have not been shown to be beneficial, but the evidence remains very limited; in the four RCTs we found, conclusions were limited due to small trial size and high withdrawal rates.
Anxiolytic drugs (mainly older generation antipsychotic drugs) may prolong the QT interval, increasing the risk of ventricular tachycardia, torsades de pointes, and sudden death. Atypical antipsychotics have been evaluated for their potential role in reducing agitation and anxiety related to refeeding, as well as for potentially increasing appetite. Weak observational evidence has suggested that they may decrease obsessiveness and agitation. However, we found no RCTs of sufficient quality on the effects of atypical antipsychotics, and further evidence from large, well-conducted RCTs is necessary to draw reliable conclusions. Some atypical antipsychotics do not appear to be associated with the same cardiac risks as older-generation antipsychotic drugs. However, further research needs to be done.
We found insufficient evidence assessing cyproheptadine for treating anorexia nervosa.
Oestrogen treatment has been hypothesized to reduce the negative effects on bone mineral density associated with anorexia nervosa. However, three small RCTs have failed to demonstrate significant changes in bone mineral density after treatment with oestrogen.
PMCID: PMC2907776  PMID: 19445758
15.  Anorexia nervosa 
Clinical Evidence  2011;2011:1011.
Introduction
Anorexia nervosa is characterised by a low body mass index (BMI), fear of gaining weight, denial of current low weight and its impact on health, and amenorrhoea. Estimated prevalence is highest in teenage girls, and up to 0.7% of this age group may be affected. While most people with anorexia nervosa recover completely or partially, about 5% die of the condition, and 20% develop a chronic eating disorder. Young women with anorexia nervosa are at increased risk of bone fractures later in life.
Methods and outcomes
We conducted a systematic review, and aimed to answer the following clinical questions: What are the effects of treatments in anorexia nervosa? What are the effects of interventions to prevent or treat complications of anorexia nervosa? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 40 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: atypical antipsychotic drugs, benzodiazepines, cyproheptadine, inpatient/outpatient treatment setting, oestrogen treatment (HRT or oral contraceptives), older-generation antipsychotic drugs, psychotherapy, refeeding, selective serotonin reuptake inhibitors (SSRIs), and tricyclic antidepressants.
Key Points
Anorexia nervosa is characterised by a low body mass index (BMI), fear of gaining weight, denial of current low weight and its impact on health, and amenorrhoea. Estimated prevalence is highest in teenage girls, and the condition may affect up to 0.7% of this group.Anorexia nervosa is related to family, sociocultural, genetic, and other biological factors. Psychiatric and personality disorders such as depression, anxiety disorders, obsessive compulsive disorder, and perfectionism are commonly found in people who have anorexia nervosa.Most people with anorexia nervosa recover completely or partially, but about 5% die from the condition and 20% develop a chronic eating disorder.Young women with anorexia nervosa are at increased risk of fractures later in life.Population assessment indicates that risks to fertility may be overstated in those who reach a healthy BMI, but children born to mothers who have recovered from anorexia nervosa seem to have lower birth weights.
There is no strong RCT evidence that any treatments work well for anorexia nervosa. However, there is a gradual accumulation of evidence suggesting that early intervention is effective. Increasing evidence suggests that working with the family may also interrupt the development of a persistent form of the illness, when this work begins early in the disease.
Evidence on the benefits of psychotherapy is unclear.
Refeeding is a necessary and effective component of treatment, but is not sufficient alone. Very limited evidence from a quasi-experimental study suggests that a lenient approach to refeeding is as effective and more acceptable compared with a more strict approach.Refeeding may be as effective in an outpatient setting as during hospital admission.Nasogastric refeeding has been used to speed up weight gain in inpatient observational studies, although it is rarely studied in RCTs. Very limited RCT evidence suggests that adding nasogastric feeding to oral nutrition can increase weight gain and reduce relapse in the short term more than oral nutrition alone, but these gains are not maintained at 1 year post-discharge. Given ethical and medical concerns with tube feeding, this approach is encouraged with caution.Nutritional supplements, including zinc, have only limited evidence for their effectiveness, and additional evaluations of these measures are warranted.
We don't know whether inpatient or outpatient treatment is more effective in people with anorexia nervosa.
Limited evidence from small RCTs has not shown significant weight gain from SSRIs or tricyclic antidepressants, some of which may cause serious adverse effects. Tricyclic antidepressants may cause drowsiness, dry mouth, blurred vision, and a prolonged QT interval in people who have anorexia nervosa. SSRIs have not been shown to be beneficial, but the evidence remains very limited; in the 4 RCTs we found, conclusions were limited because of small trial size and high rates of withdrawal.
Older-generation antipsychotic drugs may prolong the QT interval, increasing the risk of ventricular tachycardia, torsades de pointes, and sudden death. Atypical antipsychotics have been evaluated for their potential role in reducing agitation and anxiety related to refeeding, as well as for potentially increasing appetite. Increasing observational data (case series) have suggested that they may decrease obsessiveness and agitation. However, further evidence from large, well-conducted RCTs is necessary to draw reliable conclusions. Newer atypical antipsychotics, in particular olanzapine, do not seem to be associated with the same cardiac risks as older-generation antipsychotic drugs, but the known association between olanzapine and weight gain may impact compliance in people with anorexia nervosa. However, further research needs to be done.
We found insufficient RCT evidence assessing benzodiazepines or cyproheptadine for treating anorexia nervosa.
Oestrogen treatment has been hypothesised to reduce the negative effects on bone mineral density associated with anorexia nervosa. However, three small RCTs have failed to demonstrate clinically relevant changes in bone mineral density after treatment with oestrogen either HRT or oral contraceptives), and these results are supported by 2-year longitudinal data, which found similar lack of improvement.
PMCID: PMC3275304  PMID: 21481284
16.  Genome-Wide Linkage Analysis of Malaria Infection Intensity and Mild Disease 
PLoS Genetics  2007;3(3):e48.
Although balancing selection with the sickle-cell trait and other red blood cell disorders has emphasized the interaction between malaria and human genetics, no systematic approach has so far been undertaken towards a comprehensive search for human genome variants influencing malaria. By screening 2,551 families in rural Ghana, West Africa, 108 nuclear families were identified who were exposed to hyperendemic malaria transmission and were homozygous wild-type for the established malaria resistance factors of hemoglobin (Hb)S, HbC, alpha+ thalassemia, and glucose-6-phosphate-dehydrogenase deficiency. Of these families, 392 siblings aged 0.5–11 y were characterized for malaria susceptibility by closely monitoring parasite counts, malaria fever episodes, and anemia over 8 mo. An autosome-wide linkage analysis based on 10,000 single-nucleotide polymorphisms was conducted in 68 selected families including 241 siblings forming 330 sib pairs. Several regions were identified which showed evidence for linkage to the parasitological and clinical phenotypes studied, among them a prominent signal on Chromosome 10p15 obtained with malaria fever episodes (asymptotic z score = 4.37, empirical p-value = 4.0 × 10−5, locus-specific heritability of 37.7%; 95% confidence interval, 15.7%–59.7%). The identification of genetic variants underlying the linkage signals may reveal as yet unrecognized pathways influencing human resistance to malaria.
Author Summary
In tropical Africa, virtually all children become infected with malaria parasites. Most of them experience several malaria attacks per year, and over a million die from disease complications. Sickle-cell anemia, thalassemias, and other inherited red blood cell disorders indicate that malaria has selected for human genetic variants, but no attempts have so far been reported to systematically screen the human genome for malaria-resistance factors. We describe a genome-wide linkage analysis performed in children living in rural Ghana, West Africa, including approaches to select an informative study cohort and to assess, over a period of 8 mo, individual disposition to malaria parasitemia, fever episodes, and anemia. Families carrying the known malaria-protective red blood cell disorders were excluded, infection intensities were adjusted to the use of mosquito-protection devices, and parasitological and clinical findings were corrected according to the state of partial malaria immunity, which, under constant exposure, gradually develops over the first 10 y of life. The study revealed several genomic regions showing evidence for linkage to the various malaria phenotypes recorded, among them a prominent signal on Chromosome 10 correlated to the frequency of fever episodes. Future identification of genes involved is expected to reveal previously unrecognized pathways that may protect children against malaria.
doi:10.1371/journal.pgen.0030048
PMCID: PMC1829404  PMID: 17381244
17.  The MOSAIC study - comparison of the Maudsley Model of Treatment for Adults with Anorexia Nervosa (MANTRA) with Specialist Supportive Clinical Management (SSCM) in outpatients with anorexia nervosa or eating disorder not otherwise specified, anorexia nervosa type: study protocol for a randomized controlled trial 
Trials  2013;14:160.
Background
Anorexia nervosa (AN) is a biologically based serious mental disorder with high levels of mortality and disability, physical and psychological morbidity and impaired quality of life. AN is one of the leading causes of disease burden in terms of years of life lost through death or disability in young women. Psychotherapeutic interventions are the treatment of choice for AN, but the results of psychotherapy depend critically on the stage of the illness. The treatment response in adults with a chronic form of the illness is poor and drop-out from treatment is high. Despite the seriousness of the disorder the evidence-base for psychological treatment of adults with AN is extremely limited and there is no leading treatment. There is therefore an urgent need to develop more effective treatments for adults with AN. The aim of the Maudsley Outpatient Study of Treatments for Anorexia Nervosa and Related Conditions (MOSAIC) is to evaluate the efficacy and cost effectiveness of two outpatient treatments for adults with AN, Specialist Supportive Clinical Management (SSCM) and the Maudsley Model of Treatment for Adults with Anorexia Nervosa (MANTRA).
Methods/Design
138 patients meeting the inclusion criteria are randomly assigned to one of the two treatment groups (MANTRA or SSCM). All participants receive 20 once-weekly individual therapy sessions (with 10 extra weekly sessions for those who are severely ill) and four follow-up sessions with monthly spacing thereafter. There is also optional access to a dietician and extra sessions involving a family member or a close other. Body weight, eating disorder- related symptoms, neurocognitive and psychosocial measures, and service use data are measured during the course of treatment and across a one year follow up period. The primary outcome measure is body mass index (BMI) taken at twelve months after randomization.
Discussion
This multi-center study provides a large sample size, broad inclusion criteria and a follow-up period. However, the study has to contend with difficulties directly related to running a large multi-center randomized controlled trial and the psychopathology of AN. These issues are discussed.
Trial Registration
Current Controlled Trials ISRCTN67720902 - A Maudsley outpatient study of treatments for anorexia nervosa and related conditions.
doi:10.1186/1745-6215-14-160
PMCID: PMC3679869  PMID: 23721562
Anorexia nervosa; Eating disorder not otherwise specified; Outpatient treatment; Randomized controlled trial; Cost effectiveness
18.  Linkage Analysis of a Model Quantitative Trait in Humans: Finger Ridge Count Shows Significant Multivariate Linkage to 5q14.1 
PLoS Genetics  2007;3(9):e165.
The finger ridge count (a measure of pattern size) is one of the most heritable complex traits studied in humans and has been considered a model human polygenic trait in quantitative genetic analysis. Here, we report the results of the first genome-wide linkage scan for finger ridge count in a sample of 2,114 offspring from 922 nuclear families. Both univariate linkage to the absolute ridge count (a sum of all the ridge counts on all ten fingers), and multivariate linkage analyses of the counts on individual fingers, were conducted. The multivariate analyses yielded significant linkage to 5q14.1 (Logarithm of odds [LOD] = 3.34, pointwise-empirical p-value = 0.00025) that was predominantly driven by linkage to the ring, index, and middle fingers. The strongest univariate linkage was to 1q42.2 (LOD = 2.04, point-wise p-value = 0.002, genome-wide p-value = 0.29). In summary, the combination of univariate and multivariate results was more informative than simple univariate analyses alone. Patterns of quantitative trait loci factor loadings consistent with developmental fields were observed, and the simple pleiotropic model underlying the absolute ridge count was not sufficient to characterize the interrelationships between the ridge counts of individual fingers.
Author Summary
Finger ridge count (an index of the size of the fingerprint pattern) has been used as a model trait for the study of human quantitative genetics for over 80 years. Here, we present the first genome-wide linkage scan for finger ridge count in a large sample of 2,114 offspring from 922 nuclear families. Our results illustrate the increase in power and information that can be gained from a multivariate linkage analysis of ridge counts of individual fingers as compared to a univariate analysis of a summary measure (absolute ridge count). The strongest evidence for linkage was seen at 5q14.1, and the pattern of loadings was consistent with a developmental field factor whose influence is greatest on the ring finger, falling off to either side, which is consistent with previous findings that heritability for ridge count is higher for the middle three fingers. We feel that the paper will be of specific methodological interest to those conducting linkage and association analyses with summary measures. In addition, given the frequency with which this phenotype is used as a didactic example in genetics courses we feel that this paper will be of interest to the general scientific community.
doi:10.1371/journal.pgen.0030165
PMCID: PMC1994711  PMID: 17907812
19.  Association of Candidate Genes with Phenotypic Traits Relevant to Anorexia Nervosa 
European Eating Disorders Review  2011;19(6):487-493.
This analysis is a follow-up to an earlier investigation of 182 genes selected as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN). As those initial case-control results revealed no statistically significant differences in single nucleotide polymorphisms, herein we investigate alternative phenotypes associated with AN. In 1762 females using regression analyses we examined: (1) lowest illness-related attained body mass index; (2) age at menarche; (3) drive for thinness; (4) body dissatisfaction; (5) trait anxiety; (6) concern over mistakes; and (7) the anticipatory worry and pessimism vs. uninhibited optimism subscale of the harm avoidance scale. After controlling for multiple comparisons, no statistically significant results emerged. Although results must be viewed in the context of limitations of statistical power, the approach illustrates a means of potentially identifying genetic variants conferring susceptibility to AN because less complex phenotypes associated with AN are more proximal to the genotype and may be influenced by fewer genes.
doi:10.1002/erv.1138
PMCID: PMC3261131  PMID: 21780254
covariates; eating disorders; association studies; personality; genetic
20.  Bulimia nervosa 
Clinical Evidence  2010;2010:1009.
Introduction
Up to 1% of young women may have bulimia nervosa, characterised by an intense preoccupation with body weight, uncontrolled binge-eating episodes, and use of extreme measures to counteract the feared effects of overeating. People with bulimia nervosa may be of normal weight, making it difficult to diagnose. After 10 years, about half of people with bulimia nervosa will have recovered fully, one third will have made a partial recovery, and 10% to 20% will still have symptoms.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for bulimia nervosa in adults? What are the effects of discontinuing treatment in people with bulimia nervosa in remission? We searched: Medline, Embase, The Cochrane Library, and other important databases up to January 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 27 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: cognitive behavioural therapy (CBT; alone or plus exposure/response prevention enhancement), cognitive orientation therapy, dialectical behavioural therapy, discontinuing fluoxetine in people with remission, guided self-help cognitive behavioural therapy, hypnobehavioural therapy, interpersonal psychotherapy, mirtazapine, monoamine oxidase inhibitors (MAOIs), motivational enhancement therapy, pharmacotherapy plus psychotherapy, pure or unguided self-help cognitive behavioural therapy, reboxetine, selective serotonin reuptake inhibitors (SSRIs), topiramate, tricyclic antidepressants (TCAs), and venlafaxine.
Key Points
Up to 1% of young women may have bulimia nervosa, characterised by an intense preoccupation with body weight, uncontrolled binge-eating episodes, and use of extreme measures to counteract the feared effects of overeating. People with bulimia nervosa may be of normal weight, making it difficult to diagnose.Obesity has been associated with both an increased risk of bulimia nervosa and a worse prognosis, as have personality disorders and substance misuse.After 10 years, about half of people with bulimia nervosa will have recovered fully, one third will have made a partial recovery, and 10% to 20% will still have symptoms.
Cognitive behavioural therapy for bulimia nervosa (CBT-BN) may improve clinical problems of bulimia nervosa compared with no treatment, and may be as effective in reducing symptoms as interpersonal psychotherapy at 1 year, or as other psychological treatments, or antidepressants. However, we found no RCTs meeting eligibility criteria comparing the efficacy of interpersonal psychotherapy with waiting list control. We don't know whether other psychological therapies such as cognitive orientation therapy, hypnobehavioural therapy, dialectical behavioural therapy, or motivational enhancement therapy are more effective than a waiting list control at improving symptoms, as we found only a few trials. We found insufficient evidence to support enhancing CBT-BN with exposure and response prevention (ERP). Pure or unguided self-help CBT is likely to be no more effective than waiting list control at reducing binge eating. The evidence we found for guided self-help CBT is insufficient to judge this intervention because of high attrition in trials.
Some antidepressant drugs (fluoxetine, citalopram, desipramine, and imipramine) may improve symptoms in people with bulimia nervosa compared with placebo. Monoamine oxidase inhibitors (MAOIs) may increase remission rates compared with placebo, but may not reduce bulimic symptoms or depression scores.We don't know whether other antidepressants (topiramate, mirtazapine, reboxetine, or venlafaxine) can improve symptoms or remission in people with bulimia nervosa.
We don't know whether continuation of antidepressant treatment may maintain a reduction in vomiting frequency compared with withdrawing treatment in people in remission.
We don't know if combining pharmacotherapy with psychotherapy enhances outcome. Trials that have suggested combinations may enhance outcomes have been limited in power.
PMCID: PMC3275326  PMID: 21418667
21.  Genome-wide and Ordered-Subset linkage analyses provide support for autism loci on 17q and 19p with evidence of phenotypic and interlocus genetic correlates 
Background
Autism is a neurobehavioral spectrum of phenotypes characterized by deficits in the development of language and social relationships and patterns of repetitive, rigid and compulsive behaviors. Twin and family studies point to a significant genetic etiology, and several groups have performed genomic linkage screens to identify susceptibility loci.
Methods
We performed a genome-wide linkage screen in 158 combined Tufts, Vanderbilt and AGRE (Autism Genetics Research Exchange) multiplex autism families using parametric and nonparametric methods with a categorical autism diagnosis to identify loci of main effect. Hypothesizing interdependence of genetic risk factors prompted us to perform exploratory studies applying the Ordered-Subset Analysis (OSA) approach using LOD scores as the trait covariate for ranking families. We employed OSA to test for interlocus correlations between loci with LOD scores ≥1.5, and empirically determined significance of linkage in optimal OSA subsets using permutation testing. Exploring phenotypic correlates as the basis for linkage increases involved comparison of mean scores for quantitative trait-based subsets of autism between optimal subsets and the remaining families.
Results
A genome-wide screen for autism loci identified the best evidence for linkage to 17q11.2 and 19p13, with maximum multipoint heterogeneity LOD scores of 2.9 and 2.6, respectively. Suggestive linkage (LOD scores ≥1.5) at other loci included 3p, 6q, 7q, 12p, and 16p. OSA revealed positive correlations of linkage between the 19p locus and 17q, between 19p and 6q, and between 7q and 5p. While potential phenotypic correlates for these findings were not identified for the chromosome 7/5 combination, differences indicating more rapid achievement of "developmental milestones" was apparent in the chromosome 19 OSA-defined subsets for 17q and 6q. OSA was used to test the hypothesis that 19p linkage involved more rapid achievement of these milestones and it revealed significantly increased LOD* scores at 19p13.
Conclusions
Our results further support 19p13 as harboring an autism susceptibility locus, confirm other linkage findings at 17q11.2, and demonstrate the need to analyze more discreet trait-based subsets of complex phenotypes to improve ability to detect genetic effects.
doi:10.1186/1471-2350-6-1
PMCID: PMC546213  PMID: 15647115
22.  Genetic and environmental influences on eating behaviors in 2.5- and 9-year-old children: a longitudinal twin study 
Background
Eating behaviors during childhood are related both to children’s diet quality and to their weight status. A better understanding of the determinants of eating behavior during childhood is essential for carrying out effective dietary interventions.
Methods
We assessed the contribution of genetic and environmental factors to variations in selected eating behaviors in early and late childhood. Information on eating behaviors came from questionnaires administered to parents of children participating in the Quebec Newborn Twin Study when the twins were 2.5 and 9 years old (n = 692 children). Dichotomous variables were derived and analyzed using structural equation modeling, as part of a classic twin study design. We performed univariate and bivariate longitudinal analyses to quantify sources of variation and covariation across ages, for several eating behavior traits.
Results
We found moderate to strong heritability for traits related to appetite such as eating too much, not eating enough and eating too fast. Univariate analysis estimates varied from 0.71 (95% CI: 0.49, 0.87) to 0.89 (0.75, 0.96) in younger children and from 0.44 (0.18, 0.66) to 0.56 (0.28, 0.78) in older children. Bivariate longitudinal analyses indicated modest to moderate genetic correlations across ages (rA varying from 0.34 to 0.58). Common genetic influences explained 17% to 43% of the phenotypic correlation between 2.5 and 9 years for these appetite-related behaviors. In 9-year-old children, food acceptance traits, such as refusing to eat and being fussy about food, had high heritability estimates, 0.84 (0.63, 0.94) and 0.85 (0.59, 0.96) respectively, while in younger children, the shared environment (i.e., common to both twins) contributed most to phenotypic variance. Variances in meal-pattern-related behaviors were mostly explained by shared environmental influences.
Conclusions
Genetic predispositions explain a large part of the variations in traits related to appetite during childhood, though our results suggest that as children get older, appetite-related behaviors become more sensitive to environmental influences outside the home. Still, for several traits environmental influences shared by twins appear to have the largest relative importance. This finding supports the notion that familial context has considerable potential to influence the development of healthy eating habits throughout childhood.
doi:10.1186/1479-5868-10-134
PMCID: PMC4029536  PMID: 24313977
Eating behaviors; Heritability; Environmental influences; Children; Twins
23.  The Genetics of Reading Disability in an Often Excluded Sample: Novel Loci Suggested for Reading Disability in Rolandic Epilepsy 
PLoS ONE  2012;7(7):e40696.
Background
Reading disability (RD) is a common neurodevelopmental disorder with genetic basis established in families segregating “pure” dyslexia. RD commonly occurs in neurodevelopmental disorders including Rolandic Epilepsy (RE), a complex genetic disorder. We performed genomewide linkage analysis of RD in RE families, testing the hypotheses that RD in RE families is genetically heterogenenous to pure dyslexia, and shares genetic influences with other sub-phenotypes of RE.
Methods
We initially performed genome-wide linkage analysis using 1000 STR markers in 38 US families ascertained through a RE proband; most of these families were multiplex for RD. We analyzed the data by two-point and multipoint parametric LOD score methods. We then confirmed the linkage evidence in a second US dataset of 20 RE families. We also resequenced the SEMA3C gene at the 7q21 linkage locus in members of one multiplex RE/RD pedigree and the DISC1 gene in affected pedigrees at the 1q42 locus.
Results
In the discovery dataset there was suggestive evidence of linkage for RD to chromosome 7q21 (two-point LOD score 3.05, multipoint LOD 3.08) and at 1q42 (two-point LOD 2.87, multipoint LOD 3.03). Much of the linkage evidence at 7q21 derived from families of French-Canadian origin, whereas the linkage evidence at 1q42 was well distributed across all the families. There was little evidence for linkage at known dyslexia loci. Combining the discovery and confirmation datasets increased the evidence at 1q42 (two-point LOD = 3.49, multipoint HLOD = 4.70), but decreased evidence at 7q21 (two-point LOD = 2.28, multipoint HLOD  = 1.81), possibly because the replication sample did not have French Canadian representation.
Discussion
Reading disability in rolandic epilepsy has a genetic basis and may be influenced by loci at 1q42 and, in some populations, at 7q21; there is little evidence of a role for known DYX loci discovered in “pure” dyslexia pedigrees. 1q42 and 7q21 are candidate novel dyslexia loci.
doi:10.1371/journal.pone.0040696
PMCID: PMC3399896  PMID: 22815793
24.  Heritability of Cardiovascular and Personality Traits in 6,148 Sardinians 
PLoS Genetics  2006;2(8):e132.
In family studies, phenotypic similarities between relatives yield information on the overall contribution of genes to trait variation. Large samples are important for these family studies, especially when comparing heritability between subgroups such as young and old, or males and females. We recruited a cohort of 6,148 participants, aged 14–102 y, from four clustered towns in Sardinia. The cohort includes 34,469 relative pairs. To extract genetic information, we implemented software for variance components heritability analysis, designed to handle large pedigrees, analyze multiple traits simultaneously, and model heterogeneity. Here, we report heritability analyses for 98 quantitative traits, focusing on facets of personality and cardiovascular function. We also summarize results of bivariate analyses for all pairs of traits and of heterogeneity analyses for each trait. We found a significant genetic component for every trait. On average, genetic effects explained 40% of the variance for 38 blood tests, 51% for five anthropometric measures, 25% for 20 measures of cardiovascular function, and 19% for 35 personality traits. Four traits showed significant evidence for an X-linked component. Bivariate analyses suggested overlapping genetic determinants for many traits, including multiple personality facets and several traits related to the metabolic syndrome; but we found no evidence for shared genetic determinants that might underlie the reported association of some personality traits and cardiovascular risk factors. Models allowing for heterogeneity suggested that, in this cohort, the genetic variance was typically larger in females and in younger individuals, but interesting exceptions were observed. For example, narrow heritability of blood pressure was approximately 26% in individuals more than 42 y old, but only approximately 8% in younger individuals. Despite the heterogeneity in effect sizes, the same loci appear to contribute to variance in young and old, and in males and females. In summary, we find significant evidence for heritability of many medically important traits, including cardiovascular function and personality. Evidence for heterogeneity by age and sex suggests that models allowing for these differences will be important in mapping quantitative traits.
Synopsis
Genetic analysis of complex traits, which are influenced by many different variables, is difficult because different genes and environmental factors can affect each individual. To simplify analysis, the authors turned to Sardinia, one of the rare, relatively isolated populations. They recruited 6,148 participants, aged 14–102 y, from four neighboring towns. Their sample includes many related individuals, including, for example, approximately 5,000 pairs of brothers and sisters. The authors measured 98 traits in each individual, including different aspects of blood composition and several cardiovascular and personality measures.
Here, the authors evaluate the overall impact of genes and environment on each trait and show that genes can explain many of the differences and similarities between individuals. Genetic influences were typically larger in females and in younger individuals, but interesting exceptions were observed. For example, genetic factors accounted for approximately 26% of the variation in blood pressure for those more than 42 y old, but only for approximately 8% in younger individuals. Their analysis also showed that the same genetic factor could influence multiple traits, for example by affecting multiple features of personality or of cardiovascular function. DNA analyses of this cohort will eventually allow researchers to identify genes that affect each of the traits studied, including important risk factors for cardiovascular disease.
doi:10.1371/journal.pgen.0020132
PMCID: PMC1557782  PMID: 16934002
25.  Understanding the Relation between Anorexia Nervosa and Bulimia Nervosa in a Swedish National Twin Sample 
Biological psychiatry  2010;67(1):71-77.
Background
We present a bivariate twin analysis of anorexia nervosa (AN) and bulimia nervosa (BN) to determine the extent to which shared genetic and environmental factors contribute to liability to these disorders.
Method
Focusing on females from the Swedish Twin study of Adults: Genes and Environment (STAGE) (N=7000), we calculated heritability estimates for narrow and broad AN and BN and estimated their genetic correlation.
Results
In the full model, the heritability estimate for narrow AN was (a2 = .57; 95% CI: .00, .81) and for narrow BN (a2 = .62; 95% CI: .08, .70) with the remaining variance accounted for by unique environmental factors. Shared environmental factors estimates were (c2 = .00; 95% CI: .00, .67) for AN and (c2 = .00; 95% CI: .00, .40) for BN. Moderate additive genetic (.46) and unique environmental (.42) correlations between AN and BN were observed. Heritability estimates for broad AN were lower (a2 = .29; 95% CI: .04, .43) than for narrow AN, but estimates for broad BN were similar to narrow BN. The genetic correlation for broad AN and BN was .79 and the unique environmental correlation was .44.
Conclusions
We highlight the contribution of additive genetic factors to both narrow and broad AN and BN and demonstrate a moderate overlap of both genetic and unique environmental factors that influence the two conditions. Common concurrent and sequential comorbidity of AN and BN can in part be accounted for by shared genetic and environmental influences on liability although independent factors also operative.
doi:10.1016/j.biopsych.2009.08.010
PMCID: PMC2851013  PMID: 19828139

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