Modeling genetic and phenotypic data with the use of statistics Discovery of phenotypes influenced by the season of birth Can environment modify genetic effects on human anthropometric traits? Genetics of liver abnormalities in obese subjects Genetics of liver markers and their interaction with obesity “Solving biological problems that require Maths” Projects supervised by: Zoltán Kutalik Diana Marek Murielle Bochud Pedro Marques-Vidal

But des projets –Sensibiliser à une recherche clinique concrète, impliquant des notions et des données de génétique ainsi que des phénotypes, mesurés dans une population Données de génotypage (SNPs) Phénotypes Interactions avec des facteurs environnementaux Détection d'association entre un SNP et les variations d'un phénotype –Mise en pratique de théories mathématiques /statistiques permettant de modéliser la question biologique Regression linéaire et logistique Utilisation de Matlab ®

6’189 individuals Phenotypes 159 measurement 144 questions Genotypes SNPs Données: CoLaus (Cohort Lausanne) Collaboration with: Vincent Mooser (GSK), Peter Vollenweider & Gerard Waeber (CHUV)

ATTGCAATCCGTGG...ATCGAGCCA…TACGATTGCACGCCG… ATTGCAAGCCGTGG...ATCTAGCCA…TACGATTGCAAGCCG… ATTGCAATCCGTGG...ATCGAGCCA…TACGATTGCACGCCG…ATTGCAAGCCGTGG...ATCTAGCCA…TACGATTGCAAGCCG… Variants génétiques: SNPs (Single Nucleotide Polymorphisms)

What is association? chromosomeSNPstrait variant Genetic variation yields phenotypic variation Population with ‘ ’ allele Distributions of “trait”

Association using regression genotypeCoded genotype phenotype

Regression formalism (monotonic) transformation phenotype (response variable) of individual i effect size (regression coefficient) coded genotype (feature) of individual i p(β=0) error (residual) Goal: Find effect size that explains best all (potentially transformed) phenotypes as a linear function of the genotypes and estimate the probability (p-value) for the data being consistent with the null hypothesis (i.e. no effect)

Whole Genome Association

Current microarrays probe ~1M SNPs! Standard approach: Evaluate significance for association of each SNP independently: significance

Whole Genome Association significance Manhattan plot observed significance Expected significance Quantile-quantile plot Chromosome & position GWA screens include large number of statistical tests! Huge burden of correcting for multiple testing! Can detect only highly significant associations ( p < α / #(tests) ~ )

Discovery of phenotypes influenced by the season of birth Background: It has been evidenced for model organisms, e.g. mouse, that the perinatal photoperiod can have long term influence on behaviour and regulation of the Circadian clock genes. Goal: The goal of this project is to use the Cohorte Lausannois (CoLaus) data to discover phenotypes with statistical evidence of being influenced by the season of birth of the individual. Special emphasis will be on psychological traits. Mathematical tools: Statistics. The students will learn how to use Matlab to read in large data sets, conduct linear and logistic regression analysis. Biological or Medical aspects: The effect of imprinting on complex human traits is poorly understood, we aim to elucidate a special aspect of it. Supervisors: Zoltan Kutalik & Diana MarekZoltan KutalikDiana Marek References: Ciarleglio CM, Axley JC, Strauss BR, Gamble KL, and McMahon DG. Perinatal photoperiod imprints the circadian clock. Nat Neurosci 2011 Jan; 14(1) doi: /nn.2699 pmid:

Can environment modify genetic effects on human anthropometric traits? Background: Large studies (including hundreds of thousands of individuals) identified genetic factors influencing human height, body-mass- index (BMI) and waist-to-hip ratio (WHR). It is currently unknown whether the effect of the discovered genetic variants are modified by environmental factors. Goal: The goal of this project is to use the Cohorte Lausannois (CoLaus) data to find environmental factors (e.g. smoking, alcohol consumption, physical activity) that modify genetic effects influencing human height, BMI, WHR. Mathematical tools: Statistics. The students will learn how to use Matlab to read in large data sets including genetic data; conduct linear and logistic regression and interaction analysis. Biological or Medical aspects: Supervisors: Zoltan Kutalik & Diana MarekZoltan KutalikDiana Marek References: Lango Allen et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature Oct 14;467(7317):832-8.

Genetics of liver abnormalities in obese subjects Goal The goal is to perform a genome-wide association study that will potentially identify SNPs that are related to liver abnormalities in obese subjects (NAFL or NASH) by a) performing a GWAS on liver abnormalities; b) search for interactions with body mass index or obesity of the potential candidate SNPs identified; c) perform a GWAS comparing obese subjects with and without hepatic abnormalities. The tool of choice for this project is logistic regression analysis and linear regression analysis. The student will learn the basics of regressing a given phenotype to a genotype and how this analysis is implemented on a computer to handle a large number of SNPs. Supervisors Pedro Marques-Vidal & Zoltan KutalikPedro Marques-VidalZoltan Kutalik Kotronen et al. (2009) A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans. Diabetologia 52:1056–1060

Genetics of liver markers and their interaction with obesity Goal The goal is to perform a genome-wide association study that will potentially identify SNPs that are related to liver markers by a) performing a GWAS on liver markers; b) search for interactions with body mass index or alcohol consumption of the potential candidate SNPs identified; The tool of choice for this project is logistic regression analysis and linear regression analysis. The student will learn the basics of regressing a given phenotype to a genotype and how this analysis is implemented on a computer to handle a large number of SNPs. Supervisors Pedro Marques-Vidal & Zoltan KutalikPedro Marques-VidalZoltan Kutalik