Trans-ethnic polygenic risk scores for body mass index: An international hundred K+ cohorts consortium study.

Background: While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non-European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavored to develop a globally applicable trans-ethnic PRS for body mass index (BMI) through this relatively new international effort.

Methods: The polygenic risk score (PRS) model was developed, trained and tested at the Center for Applied Genomics (CAG) of The Children's Hospital of Philadelphia (CHOP) based on a BMI meta-analysis from the GIANT consortium.

Trans-ethnic Polygenic Risk Scores for Body Mass Index: An International Hundred K+ Cohorts Consortium Study.

Background: While polygenic risk scores hold significant promise in estimating an individual's risk of developing a complex trait such as obesity, their application in the clinic has, to date, been limited by a lack of data from non-European populations. As a collaboration model of the International Hundred K+ Cohorts Consortium (IHCC), we endeavored to develop a globally applicable trans-ethnic PRS for body mass index (BMI) through this relatively new international effort.

Methods: The PRS model was developed trained and tested at the Center for Applied Genomics (CAG) of The Children's Hospital of Philadelphia (CHOP) based on a BMI meta-analysis from the GIANT consortium.

Identification of Genetic Loci Shared Between Attention-Deficit/Hyperactivity Disorder, Intelligence, and Educational Attainment.

Background: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that is consistently associated with lower levels of educational attainment. A recent large genome-wide association study identified common gene variants associated with ADHD, but most of the genetic architecture remains unknown.

Methods: We analyzed independent genome-wide association study summary statistics for ADHD (19,099 cases and 34,194 controls), educational attainment (N = 842,499), and general intelligence (N = 269,867) using a conditional/conjunctional false discovery rate (FDR) statistical framework that increases power of discovery by conditioning the FDR on overlapping associations.

Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable common childhood-onset neurodevelopmental disorder. Some rare copy number variations (CNVs) affect multiple neurodevelopmental disorders such as intellectual disability, autism spectrum disorders (ASD), schizophrenia and ADHD. The aim of this study is to determine to what extent ADHD shares high risk CNV alleles with schizophrenia and ASD.

Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa.

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness, affecting 0.9-4% of women and 0.3% of men, with twin-based heritability estimates of 50-60%.

No link between X chromosome inactivation pattern and simple goiter in females: evidence from a twin study.

Background: Simple goiter (SG) comprises diffuse (DG) and nodular (NG) benign nonautoimmune nontoxic goiter. In nonendemic goiter areas, the ratio of females to males may exceed 5:1, indicating that gender and/or sex hormones may play a role in the etiology of SG in these areas. Theoretically, as shown for autoimmune thyroid disease, X chromosome inactivation (XCI) and resultant tissue chimerism could offer a novel explanation for the female preponderance of SG.

Severe hypohidrotic ectodermal dysplasia in a girl caused by a de novo 9;X insertion that includes XIST and disrupts the EDA gene.

X-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by mutations in the EDA gene. A girl with severe hypohidrotic ectodermal dysplasia and normal mental development had completely skewed X chromosome inactivation with only the paternal X active in peripheral blood cells. Routine chromosome analysis and sequencing of the EDA gene were normal.

Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers.

Rett syndrome is a largely sporadic, X-linked neurological disorder with a characteristic phenotype, but which exhibits substantial phenotypic variability. This variability has been partly attributed to an effect of X chromosome inactivation (XCI). There have been conflicting reports regarding incidence of skewed X inactivation in Rett syndrome.

High frequency of skewed X-chromosome inactivation in females with autoimmune thyroid disease: a possible explanation for the female predisposition to thyroid autoimmunity.

Context: Autoimmune thyroid diseases (AITD) comprise Graves' disease (GD) and Hashimoto's thyroiditis (HT). They are characterized by loss of immunological self-tolerance and female preponderance. Theoretically, X chromosome inactivation (XCI) and resultant tissue chimerism could offer an explanation for the female predisposition to AITD.

Dimensional phenotypic analysis and functional categorisation of mutations reveal novel genotype-phenotype associations in Rett syndrome.

We aimed to improve the understanding of genotype-phenotype correlations in Rett syndrome (RS) by adopting a novel approach to categorising phenotypic dimensions - separating typicality of presentation, outcome severity and age of onset - and by classifying MECP2 mutations strictly by predicted functional attributes. MECP2 mutation screening results were available on 190 patients with a clinical diagnosis of RS (140 cases with classic RS, 50 with atypical RS). 135 cases had identified mutations.

Twin study of genetic and aging effects on X chromosome inactivation.

To investigate the genetic influence on X chromosome inactivation and on age-related skewing of X inactivation, in particular, we analysed the X inactivation pattern (XIP) in peripheral blood cells from 118 young monozygotic (MZ) twin pairs (18-53 years), 82 elderly MZ twin pairs (55-94 years), 146 young dizygotic (DZ) twin pairs (20-54 years) and 112 elderly DZ twin pairs (64-95 years). Elderly twins had a higher frequency of skewed X inactivation (34%) than young twins (15%) (P<0.001).

Situs ambiguus in a female fetus with balanced (X;21) translocation--evidence for functional nullisomy of the ZIC3 gene?

The human ZIC3 gene has been mapped to Xq26.2, the visceral heterotaxy locus HTX1, and has been shown to be mutated in X-linked situs ambiguus and/or complex heart defects. We report on a female fetus with situs ambiguus, asplenia and corrected transposition of the great arteries, displaying a (X;21) translocation.