Faculty Bibliography

Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.

Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

Hirschsprung disease (HSCR, aganglionic megacolon) represents the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has importantly decreased mortality and morbidity which allowed the emergence of familial cases. Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment. While all Mendelian modes of inheritance have been described in syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. The tyrosine kinase receptor RET is the major gene with both rare coding sequence mutations and/or a frequent variant located in an enhancer element predisposing to the disease. Hitherto, 10 genes and five loci have been found to be involved in HSCR development.

Genomic changes such as copy number alterations are one of the major underlying causes of human phenotypic variation among normal and disease subjects. Array comparative genomic hybridization (CGH) technology was developed to detect copy number changes in a high-throughput fashion. However, this technology provides only a >30-kb resolution, which limits the ability to detect copy number alterations spanning small regions. Higher resolution technologies such as single nucleotide polymorphism (SNP) microarrays allow detection of copy number alterations at least as small as several thousand base pairs. Unfortunately, strong probe effects and variation introduced by sample preparation procedures have made single-point copy number estimates too imprecise to be useful. Various groups have proposed statistical procedures that pool data from neighboring locations to successfully improve precision. However, these procedure need to average across relatively large regions to work effectively, thus greatly reducing resolution. Recently, regression-type models that account for probe effects have been proposed and appear to improve accuracy as well as precision. In this paper, we propose a mixture model solution, specifically designed for single-point estimation, that provides various advantages over the existing methodology. We use a 314-sample database, to motivate and fit models for the conditional distribution of the observed intensities given allele-specific copy number. We can then compute posterior probabilities that provide a useful prediction rule as well as a confidence measure for each call. Software to implement this procedure will be available in the Bioconductor oligo package (www.bioconductor.org).