Litteratur. Lärandemål för undervisningstillfälle. Lecture Overview. Basic principles The twin design The adoption design

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1 Litteratur Behavioral Genetics Twin and Adoptions studies Twin and adoption methods (Kapitel 5; sid 70-91) Henrik Larsson MEB Lärandemål för undervisningstillfälle - Studenten ska kunna redogöra för kvantitativa-genetiska metoder för att studera genetiska effekter för komplexa beteenden och sjukdomar - Beräkna betydelsen av arv (heritabilitet) och miljö utifrån statistiska exempel Lecture Overview Basic principles The twin design The adoption design - Studenten ska kunna tolka och utvärdera resultat (tex Heritabilitet) från tvilling/adoptionsstudier 1

2 Basic principles Quantitative genetics focuses on naturally occurring variation in the population Quantitative genetics focuses on the similarity/resemblance between relatives to obtain information about the relative importance genetic and environmental factors Variation IQ Personality Heart rate Blood pressure BMI Weight Height Etc, etc Why do we see this variation? One of the factors that makes individuals different is genetic variation Low Average High Similarity/resemblance Similarity/resemblance: Genetic relatedness Great-grandfathers (12.5%)c Quantitative genetic methods compare the similarity of family members who share different levels of genes and environment. If pairs of individuals who share more of their genes are more similar il to each other than pairs of individuals who share fewer of their genes, this suggests there is a genetic influence on those phenotypes. Half brothers (25%) Brothers (50%) Nephews (25%) Grandfathers (25%)c Father (50%) Index case Sons (50%)c Great-Uncles (12.5%) Uncles (25%) Identical twin (100%) First cousins (12.5%) If pairs of individuals who share their environment resemble one another more than those who do not, this suggests an influence of shared environment. Greatnephews (12.5%) Grandsons (25%) Great-grandsons (12.5%) 2

3 s1 s1 y1 Similarity/resemblance Measuring similarity via correlations Correlations Similarity/resemblance Measuring similarity via correlations Family resemblance for cognitive ability s s y Similarity/resemblance Measuring similarity via concordance Similarity/resemblance Measuring similarity via concordance Family resemblance for Schizophrenia Because disorders are diagnosed as either or dichotomies, familial resemblance is assessed by concordance rates (an index of risk) rather than by correlations E.g., if sibling concordance is 10% for a disorder, we say that siblings of probands have a 10% risk for the disorder 3

4 The Quantitative genetic model We typically split variance into: Additive genetics (heritability) Common environment (shared environment) Environment specific to each twin (nonshared environment) Additive genetics Individual differences caused by the independent effects of alleles or loci that add up. In contrast to non-additive genetic variance, in which the effects of alleles or loci interact. We typically split variance into: Common Environment Environmental factors responsible for resemblance between family members We typically split variance into: Environment specific to each twin Environmental influences that contribute to differences between family members 4

5 Heritability The proportion of observed (phenotypic) differences among individuals that can be statistically attributed to genetic differences Interpreting heritability Genetic and environmental contributions to a phenotype do not refer to a single individual, just as the area of a single rectangle cannot be attributed to the relative contributions of length and width, because area is the product of length and width Answers the question: how important are genetic differences for individual differences? Interpreting heritability Genetic and environmental contributions to a phenotype do not refer to a single individual, just as the area of a single rectangle cannot be attributed to the relative contributions of length and width, because area is the product of length and width Interpreting heritability Genetic and environmental contributions to a phenotype do not refer to a single individual, just as the area of a single rectangle cannot be attributed to the relative contributions of length and width, because area is the product of length and width 5

6 Interpreting heritability Genetic and environmental contributions to a phenotype do not refer to a single individual, just as the area of a single rectangle cannot be attributed to the relative contributions of length and width, because area is the product of length and width Interpreting heritability Heritability: Refers to genetic variation, but does not provide information regarding the number of genes Is a population statistic Does not refer to a particular individual Does not refer to group differences Does not imply genetic determinism Lecture Overview Two types of twins Basic principles The twin design The adoption design DZ MZ 6

7 How do we know if twins are identical or non-identical? How do we know if twins are identical or non-identical? 1) DNA markers (if twins differ for on any DNA markers they must be fraternal twins) 2) Appearance (even the single question Are you alike like two peas in a pod? produces >90% accuracy when compared to DNA markers)! The Twin Design Comparison of identical and non-identical twins The Twin Design Comparison of identical and non-identical twins What makes identical twins similar? Shared genes (100%) What makes identical twins different? Shared environment What makes non-identical twins similar? Non shared environment Shared genes (50%) Shared environment 7

8 The Twin Design The Twin Design Genetic influence (A) = identical twins > fraternal twins The greater resemblance would be expected based on MZ twins sharing all their segregating genes MZ DZ MZ DZ Shared environmental influence (C)= environmental influence that makes family members similar to each other Non-identical twins more similar than expected by genetic relatedness MZ DZ MZ DZ The Twin Design Quantitative Genetic Analyses of Twin Data Non-shared environmental influence (E) = environmental 80 influences that make family 70 members different from each 60 other 50 Identical twins not 100% identical Measurement error MZ DZ MZ DZ What does A + C + E =? The full variance This is usually standardized to 1 8

9 Now it s your turn... rmz = A + C rdz =.5A + C rmz - rdz =.5A rmz = 0.8 rdz = 0.6 rmz - rdz = 0.2 Type of twins Intraclass correlation 1) MZ.60 DZ.60 Effects A C E A = 2(rMZ-rDZ) A = 0.4 2) MZ.60 DZ.30 C = rmz - A C = 0.4 3) MZ.80 DZ.50 E = 1 - rmz E = 0.2 Structural Equation Modelling Complex models rely on MZ = 1.0 DZ = 0.5 MZ = 1.0 DZ = 1.0 A C E A C E A1 C1 E1 A1 C1 E1 Twin 1 Twin 2 Mx Graphical User Interface 9

10 About MX Assumptions of the twin method Low power when comparing correlations Model fitting can compare more than two groups (uses all available data) Give us information about goodness of fit Compare models Can test hypotheses Mating is random in the population Assortative mating means nonrandom mating that results in similarity between spouses Equal Environment Assumption Environmental factors relevant to traits under study are the same for both types of twins Mating is random in the population Do individuals who mate tend to be similar? Height =.25 Weight =.20 Personality = IQ/cognitive ability =.40 Education =.60 Important for genetic research! - Increases genetic variance in the population - Increases correlations for first-degree relatives (including DZ twins), but does not affect MZ correlations = underestimate heritability Equal Environment Assumption Tests of the Equal Environment Assumption: MZ twins whose parents mistakenly thought them to be DZ twins were not less alike behaviorally than those who were correctly classified as MZ twins MZ t i h d d lik h h d th MZ twins who were dressed alike, or who had the same teachers were not more behaviorally alike than those who did not. 10

11 Generalisability Generalisability of twins Are twins representative of the general population? Twins more likely to.. - Be born prematurely - Experience adverse intrauterine environments - Have lower birth weight - Have slower childhood language development It depends on what we want to study! BUT, twins are similar to non-twins on most traits Beyond heritability Multivariate/Longitudinal twin models Multivariate quantitative genetic modelling can tell us about origins of co-morbidity and the development course MZ and DZ resemblance compared across phenotypes/ages Correlate Twin 1 s measure of phenotype/time 1 with Twin 2 s measure of phenotype/time 2 If Twin 1 Twin 2 resemblance across phenotype/time is stronger for MZ than DZ twins, then there are genetic influences on phenotypic overlap/stability 11

12 Lecture Overview Basic principles The twin design The adoption design Adoption design The adoption design untangles genetic and environmental causes of family resemblance The first adoption study, which investigated IQ, was reported in 1924 The first adoption study of schizophrenia was reported in 1966 Adoption studies have become more difficult to conduct as the number of adoptions has declined Less frequent as contraception and abortion increased, and more unmarried mothers kept their infant But still plenty of well conducted adoption studies Adoption design Adoption design Genetic-plus-environmental relatives Adoption Genetic relatives Environmental relatives In the twin design, inference on the existence and magnitude of shared environmental effects is indirect, being based on a comparison of MZ and DZ correlations, and may lack statistical power The adoptive sibling correlation provides a more direct assessment of shared environmental influences 12

13 Family resemblance for cognitive ability Assumptions of the adoption design Correlation 0,5 0,45 0,4 0,35 0,3 0,25 0,2 0,15 0,1 0,05 0 0,42 0,47 Sibling 0,24 0,24 Sibling 0,2 Parentoffspring Parentoffspring Parentoffspring 0,32 Sibling Representativeness Prenatal environment Selective placement Genetic-plusenvironmental Genetic Environmental Representativeness Are the: biological parents adoptive parents adopted children representative of the general population? Prenatal environment It is assumed that adopted children are only similar to their birth mothers because of shared genes. However, birth mothers provide the prenatal environmental for their adopted-away away children! Prenatal effects can be tested independently from postnatal environment by comparing correlations for birth mothers and birth fathers 13

14 Selective placement If biological and adoptive parents are matched then the validity of adoption studies may be questioned. E.g. children may be similar to their biological parents for environmental reasons as well as genetic reasons.. However, there is little evidence of selective placement 14