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Applying the method to a large anthropometric GWAS meta-analysis (from the Genetic Investigation of Anthropometric Traits consortium study), we show that for height, body mass index (BMI), and waist-to-hip ratio (WHR) substantial additional phenotypic variance can be explained compared to what obtained via single SNP association. The method also permitted an increase (by up to 50%) in the number of loci that replicate in a discovery-validation design. Specifically, we identified 74 loci at which the multi-SNP, a linear combination of SNPs, explains significantly more variance than does the best individual SNP. A detailed analysis of multi-SNPs shows that most of the additional variability explained is derived from SNPs that are not in linkage disequilibrium with the lead SNP, suggesting a major contribution of allelic heterogeneity to the missing heritability.

Our results were published in the 2012 November issue of the American Journal of Human Genetics. A Matlab package that implements the method is also available here.

Lay summary (in French) is available both at the University of Lausanne news site and that of the University Hospital (CHUV).

Only a fraction of patients with chronic HCV infection develop liver fibrosis, a process that might also be affected by genetic factors. We studied well-characterized HCV-infected patients of European descent who underwent liver biopsies before treatment.

We defined various liver fibrosis phenotypes on the basis of METAVIR scores, with and without taking the duration of HCV infection into account. Our GWA analyses were conducted on a primary cohort of ~1200 patients using 780K single nucleotide polymorphisms (SNPs). We genotyped 96 SNPs with P values <5 × 10⁻⁵ from an independent replication cohort of ~1200 patients. In the combined cohort of ~2400 HCV-infected patients, the SNPs rs16851720 (in the total sample) and rs4374383 (in patients who received blood transfusions) were associated with fibrosis progression (P_combined = 8.9 × 10⁻⁹ and 1.1 × 10⁻⁹, respectively). The SNP rs16851720 is located within RNF7, which encodes an antioxidant that protects against apoptosis. SNP rs4374383 is linked to the functionally related gene MERTK, which encode factors involved in phagocytosis of apoptotic cells by macrophages. Our GWA study identified several susceptibility loci for HCV-induced liver fibrosis; these were linked to genes that regulate apoptosis. Apoptotic control might therefore be involved in liver fibrosis.

Compared to previous approaches, the novelty of our method is that it (a) does not require having an independent (unbiased) estimate of the effect sizes; (b) makes use of the complete distribution of P-values while allowing for the false discovery rate; (c) takes into account allelic heterogeneity and the SNP pruning strategy. We applied our method to the latest GWAS meta-analysis results of the GIANT consortium. It revealed that while the explained variance of genome-wide (GW) significant SNPs is around 1% for waist-hip ratio (WHR), the observed P-values provide evidence for the existence of variants explaining 10% (CI=[8.5–11.5%]) of the phenotypic variance in total. Similarly, the total explained variance likely to exist for height is estimated to be 29% (CI=[28–30%]), three times higher than what the observed GW significant SNPs give rise to. This methodology also enables us to predict the benefit of future GWA studies that aim to reveal more associated genetic markers via increased sample size. For more details click here.

A simple Matlab package of the algorithm can be downloaded from here. Read, modify and launch the main.m file.

Our group – as the analyst of the CoLaus and Hypergenes cohorts – provided genome-wide association summary statistics for the meta-analytic effort of the GIANT consortium. The meta-analysis used 183,727 individuals to reveal 180 loci harbouring genetic variants associated with adult height. These variants are clustered in genomic loci and biological pathways.

A further association analysis of 249,796 individuals revealed 18 new loci associated with body mass index. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.

Finally, a meta-analysis identified 13 new loci associated with waist-hip ratio. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men. These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.