1. Quantitative genetics petercelec@gmail.com www.imbm.sk

2. Basics Genotype affects phenotype Hardy-Weinberg equilibrium... Mendelian genetics is easy...but it works only rarely Selection, mutation, drift...

3. Happiness Always...do literature search Environmental factors –... Genetic factors???

4. Issues Who is happy? Is it binary or continuous? How to measure it? How to analyze genetic effects? How to find the the genetic factors?

5. Quantitative genetics Non-Mendelian inheritance Polygenic traits – Many genes – Continuous variability Categorical, treshold parameters Multifactorial traits – Polygenic – Environmental factors

6. Gauss curve

7. Genetic basis for the Gauss curve

8. Panmixia vs inbreeding Selective vs non-selective mating Inbreeding disturbs normal distribution – Median=mean=modus – Symmetric histogram Decrease of heterozygosity Reduced fitness

9. Heritability P = G + E + GxE G = A + D + I E = C + E G - Genetic factors, E - environmental factors, GxE - interactions, A - additive effects, D – dominance (alleles at one locus), E – epistasis (alles at different loci), C - common and E - non-shared environment (children in one family are different) EEE...

10. Heritability Variability 1 = a 2 + d 2 + i 2 + c 2 + e 2 + interactions Heritability – h 2 =genetic variability/phenotypic variability – narrow h 2 = a 2 – broad H 2 = a 2 + d 2 + i 2

11. Heritability Proportion of phenotypic variability attributable to genetic variability Examples A statistical parameter – population measure Do not use for individuals Not a constant (place, time, population) Not specific Itself highly affected by environment Low reproducibility

12. Heritability Does not mean familial occurence – Genetic factors – Cultural factors – Socioeconomic variables – Chance!!! Does not mean unmodifiable – Diabetes Does not mean inherited! – Down syndrome, autism

13. Heritability Correlations – cor(P 1,P 2 ) = r a a 2 + r d d 2 + r i i 2 + r c c 2 Interactions – Passive (born into), active (extroversion), reactive – evocative (attractive) – Phenylketonuria – Effect of age – Effect of socioeconomical status Heritability and selection – Low heritability – inefficient selection

14. IQ variability Bouchard & McGue, 2003

15. IQ variability Turkheimer et al, 2003.

16. Happiness

17. Scientific approaches Twin studies Adoption studies Linkage analysis Case-control studies – Candidate gene approach – Genome-wide association studies

18. Twin studies Twins – Monozygotic MZ (100% genetic relatedness) – Dizygotic DZ (50% genetic relatedness) – Concordance of traits – r MZ > r DZ – r MZ = r DZ – r MZ < 1

19. Twin studies Heritability – r mz = A + C – r dz = ½A + C – A = 2 (r mz – r dz ) – C = r mz – A = 2 r dz – r mz – E = 1 – r mz

20. Twin studies

22. – Environmental relatedness? Monochorionic (2/3 MZ), dichorionic (1/3 MZ, all DZ)

23. Twin studies

24. Adoption studies Genes vs environment Biological parents vs adoptive parents Cave: – prenatal development – selective placement – questionable representativness

25. QTL Quantitive trait locus/loci Search for specific genetic factors Locations at chromosomes, not genes SNP or CNV marker in linkage

26. McCarthy et al, 2008

27. GWAS Cases and controls – binarization Frequent genotypes with small effects Large numbers – Study power – sample size Bias – false positive results – why? Quality control (samples and SNP calling) Replication Validation

31. GWAS results presentation Quantile – quantile plots Manhattan plots

32. Happiness Twin and adoption studies – Estimates of heritability Linkage analysis and GWAS – Search for genetic factors Experiments – Mechanism of action – Interpretation of animal experiments – Ethics

33. Test

34. Psychometry Well being questionnaire http://www.who-5.org/ Valid? Precise? Specific? Sensitive? Reproducible?

35. Statistics Tests Correlation Regression Confidence intervals