Quantitative Genetics and Twin Studies

Transcription

1 Count Count Count Count Quntittive Genetics nd Twin Studies n Introduction! co de Geus -Dept. Biologicl Psychology -Netherlnds Twin Register msterdm, the Netherlnds 600 N = 6602 M = 48,27 SD = 25,0 75 N = 794 M = 84,76 SD=, Individul differences PQ neuroticism N =423 M = 9,9 SD= 7, mbultory hert rte (morning) N = 698 M = 8,22 SD= 8, Distolic BP rectivity (Tone voidnce RT tsk) 0 0,00 20,00 30,00 40,00 Cortisol t wkening

2 Vrince Components Phenotype = µ + G + + G* Vrince (P) = vr (µ +G + + G*) = vr(g) + vr() + vr(g*) + 2Cov(G,)+2Cov(G,G*)+2Cov(,G*) ll G covs set to zero: = vr (G) + vr () + vr (G*) vr(g*) set to zero: Vr(P) = vr(g) + vr() llelic vrition llele of Fther Mother 2 4 (C) 3 C3 (C) 9 C9 Gene = unit of heredity Locus = loction (of gene) on chromosome llele = different vrints of the gene t the sme locus Homozygous genotype = pternl nd mternl lleles re identicl Heterozygous genotype = pternl nd mternl lleles re different

3 Dichotomous trits: Huntington s disese x H h h h Genotypes: ¼Hh ¼Hh ¼hh ¼hh ffected Unffected MIM4300 (993) 4p6.3 dysfunctionl Huntingtin protein Dominnt disese Dichotomous trits: PKU x P p P p Genotypes: ¼PP ¼Pp ¼ pp ¼ pp Unffected, 2 Crriers ffected MIM26600 (984) 2q24. dysfunctionl Phenyllnine dehydroxylse Recessive disese

4 Quntittive trits llele of Fther Mother b B 2 C3 4 C9 Regultory zone b..b incresing lleles for better trnscription: more protein synthesis xon 2..4 incresing lleles for more efficient isoform of the protein xon 5 C..C9 incresing lleles for dysfunctionl protein - d = bb Bb m (79) 9 = -2 = +2 BB xmple: stture gene with bi-llelic polymorphism in the regultory zone of growth protein yields three types of persons with three different heights: 67, 75, 9 cm. breeding (thought!) experiment P homozygote seletion (BB fthers * bb mothers) => F, ll Bb F intercross (Bb fthers * Bb mothers) => F2, BB, Bb, bb Genotype (i) BB Bb bb Frequency (f) ¼ ½ ¼ Genotypic effect (x) d - f * x ¼ ½ d -¼ Men genetic effect (µ g ) = f i *x i = 2*¼ + -4*½ + -2*¼ = -2 Genetic vrince = f i *(x-µ g ) 2 vr(p) = vr() Vr + (G) vr (D) + vr() =¼*(2--2) 2 + ½*( ) 2 + ¼*( ) 2 =76 The contribution of the stture locus to the genetic vrince in stture

5 Polygenetic trits For multiple genes, dditive or dominnt, with vrying llelic frequencies, genetic effects on the sme trit my be summed nd cn be shown - under the centrl limit theorem - to yield normlly distributed men genetic effect with vrince Vr() + Vr(D). = B = C = smll effect 2 = B2 = C2 = lrge effect Heritbility How do we estblish the reltive contribution of genetic influences to trit vrince (.k.. Heritbility or H 2 )?? Fmily studies to test the strength of the correltion between genetic reltedness nd trit resemblnce!

6 Fmilil resemblnce in disese trits Popultion Hlf Sibling Grnd child Nephew/Niece Uncle/unt Full Sibling Children Prents 0% genetic resemblnce 25% genetic resemblnce 50% genetic resemblnce Schizophreni Prevlence Fmilil resemblnce in quntittive trits Tmbs et l. (992) collected resting blood pressure in Norwegins from three genertions

7 Shred (fmily) environment Fmily members shre prt of their environment (SS, Neighborhood, Diet, Prentl rering style, School, etc.). This common environment cn lso contribute to fmily resemblnce!! Vr(P) = vr () + vr (D) + vr () = vr () + vr (D) + vr (C) + vr () C = common environment = unique environment Monozygotic MZ twins re 00% geneticlly identicl

8 Dizygotic DZ twins (nd singleton siblings) shre on verge 50% of their genetic vrition. Clssicl Twin design The clssicl twin design for disese trits dtes from the 920's, when dignosis of monozygotic (MZ) nd dizygotic (DZ) twins becme relible. It is ssumed tht twins in the sme household re exposed to shred environmentl risk fctors to the sme extent whether they re MZ or DZ. Under the equl environment ssumption, differences in intrpir resemblnce by zygosity reflect genetic rther thn common environmentl fctors.

9 Intrpir twin correltion for stture MZ mles rmz= 0,95 Rndom sme-ged mle pirs 20 stture twin stture twin DZ mles rdz = 0, stture stture dolescent Dutch twins, 5-9 yr stture twin stture twin Twin correltions: rules of thumb Vr () / totl Vr (P) = 2 = 2 (rmz - rdz) Vr () / totl Vr (P) = e 2 = rmz Vr (C) / totl Vr (P) = c 2 = 2rDZ - rmz Vr (D) / totl Vr (P) = d 2 = 2rMZ - 4rDZ compliction: Vrince = + D + C + ; MZ covrince: + D + C; DZ covrince: ½ + ¼ D + C 3 equtions, 4 unknowns D&C cnnot be estimted simultneously, either C or D hs to be ssumed to be 0. Usully, D is modeled only if MZ >> 2*DZ.

10 Heritbility of stture Intrpir correltions: Monozygotic: rmz= 0,95 Dizygotic: rdz = 0,60 = 2 * ( ) = 0.70 C = 2 * = 0.25 = 0.95 = 0.05 D = 2 * * 0.60 = -0.50! % individul vrince explined by Heritbility: 70 % nvironmentl influences: 30 % (shred 25%, unique 5%) Univrite pth model for twin studies r MZ = r DZ/sib = r MZ =, r DZ/sib = 0.5 C C e c c e Stture Twin Stture Twin 2 Cov (MZ) = (**) + (c**c) = 2 +c 2 Cov (DZ) = (*0.5*) + (c**c) = c 2 Vr (stture) = (**) + (c**c) + (e**e) = 2 + c 2 + e 2

11 Model fitting Model C 0.5/ C lterntive models compred by likelihoodrtio tests. e c P c e P2 Model 2 0.5/ e P ge Model 3 P2 e Model 4: No sex differences Genetic nlysis of stture: Wht is the best model? Model Chi df p. ge, Genes, C, (sex dif) ge, Genes, (sex diff) ge, Genes, (no sex diff) Best model: (no C) with sex differences: Mles Femles Genes 75% 89% Unique nvironment 5% 0% ge 20% % (NB 5-9!)

12 s: r MZ =, r DZ/sib = 0.5 C s: r MZ = r DZ/sib = Multivrite extension C C 2 2 C C 2 2 c c 22 c 2 2 c c c 22 Stture Twin e Weight Twin e 22 Stture Twin 2 e e 2 e 2 Weight Twin 2 e Genetics of trcking: mplifiction or emergence of new genes I = 2 = n = II = 2 = 2 n = 0.5 III 22 > 0 nn > 0 2 n 2 22 n2 nn n.

13 sy to dd observed genotypes on mrkers or cndidte genes r MZ = r DZ/sib = r MZ =, r DZ/sib = 0.5 e C c r MZ =, r DZ/sib = π^ C c e Q Q q q P twin P twin2 Q = Quntittive Trit Locus, mesured genotype π =IBD/2, mesure for sib resemblnce t the QTL Not limited to twin reserch! r sib = 0.5 e r sib = π^ e Q Q q q P sib P sib2