Which of these phenotypes share the same genetic influences?

Pleiotropy: Textbook Example Cystic Fibrosis, simple autosomal recessive One gene influences multiple organs: lungs, liver, pancreas, small intestine, reproductive tract, skin (sweat glands)

Trait 1 V A Trait 2 V A No Pleiotropy

Trait 1 V A Trait 2 V A Partial Pleiotropy

Trait 1 V A Trait 2 V A Complete Pleiotropy

Phenotypic correlations can be broken down into genetic and environmental components  P  h 1 2 h 2 2  G  1  h  h 2 2  E h 1 2 and h 2 2 = heritabilities for traits 1 and 2  P = phenotypic correlation  G = additive genetic correlation  E = environmental correlation

Extension to multivariate analysis   G  2  +E  I  =Kronecker product operator E=residual environment covariance matrix G=additive genetic covariance matrix

Nested models for bivariate analyses Parameters estimated Model  e1 &  e2  a1 &  a2  e  g General additive++++ No pleiotropy+++0 Complete pleiotropy+++1

Examples from the GAIT Project.

Phenotypic correlations can be broken down into genetic and environmental components  P  h 1 2 h 2 2  G  1  h  h 2 2  E h 1 2 and h 2 2 = heritabilities for traits 1 and 2  P = phenotypic correlation  G = additive genetic correlation  E = environmental correlation

Phenotypic correlations among vitamin K dependent proteins. FVIIFIXFXPCtPSfPS FII FVII FIX FX Protein C Total Protein S0.63

Genetic and environmental correlations among vitamin K dependent proteins. FIIFVIIFIXFXPCtPSfPS FII FVII FIX FX Protein C Total PS Free PS

t Discrete (disease) Continuous (liability) 01

Trait  p  g  e APCR-0.23*-0.65*0.67* FVII * FVIII0.29*0.69*-0.13 FIX *-0.20 FXI0.21*0.56*0.07 FXII0.17*0.35*-0.15 Homocysteine0.23*0.65*-0.28 t-PA0.18*0.75*-0.10 vWF0.26*0.73*-0.18 Correlations with liability to thrombosis

Genetic correlations Liability toAPCR Thrombosis Factor VIII levels ±0.12 p = ± 0.14 p = ± 0.15 p =

Inference A single gene or set of genes influences variation in risk for thrombosis, factor VIII levels, von Willebrand factor levels, and activated protein C resistance. However, each of these traits is also affected by additional genes not shared with the others.

Genetic correlations Liability to Thrombosis HomocysteineAPCR Factor VIII 0.65 ± 0.20 p = ± ± 0.23

Inference Evidence exits for a single gene or set of genes which influences both homocysteine levels and risk for thrombosis. This is a different gene or set of genes than the one with common influences on factor VIII, vWF, APCR, and thrombosis.

Another way of looking at  G FXII - liability  G = 0.35, h2 = 0.68 for FXII, 0.61 for liability 12.25% of genetic variance shared in common (i.e.  G squared) FXII: 8.3% of variance genes shared w/ liability, 59.7% of variance genes not shared w/liability Liability: 7.5% of variance genes shared w/FXII, 53.5% of variance genes not shared w/FXII

Extension to multivariate analysis  Q  ˆ  G  2  +E  I  =Kronecker product operator Q=additive genetic covariance matrix for QTL G=residual additive genetic covariance matrix E=environmental covariance matrix

Nested models for bivariate analyses Parameters estimated Model  e1 &  e2  a1 &  a2  q1 &  q2  e  g  q Sporadic+00+ Additive++0++ Linkage Pleiotropy Coincident+++++0

Pleiotropy: a single gene influencing two or more phenotypes,  q = 1 or -1 Coincident Linkage: two closely placed genes, each influencing different phenotypes,  q = 0

Why do multivariate linkage analysis? Exploits pleiotropy to improve power to detect linkage Allows a formal test of pleiotropy versus coincident linkage Improves estimate of QTL location and effect size

Trait  p  g  e APCR-0.23*-0.65*0.67* FVII * FVIII0.29*0.69*-0.13 FIX *-0.20 FXI0.21*0.56*0.07 FXII0.17*0.35*-0.15 Homocysteine0.23*0.65*-0.28 t-PA0.18*0.75*-0.10 vWF0.26*0.73*-0.18 Correlations with liability to thrombosis

Results of FXII genome screen (LODs > 1) LocationLOD Ch 5, 193 cM4.73 Ch 10, 38 cM3.53 Ch 2, 9 cM2.26 Ch 11, 10 cM1.30 Ch 14, 63 cM1.16 Ch 15, 79 cM1.03

FXII – Chromosome 10 QTL

FXII – Chromosome 5 QTL

FXII levels are genetically correlated with risk of thrombosis. Do either of the QTLs detected through FXII levels influence liability to thrombosis?

Does the QTL identified through trait1 also influence trait2? Parameters estimated Model  e1 &  e2  a1 &  a2  q1 &  q2  e  g  q No pleiotropy+++/0++ Pleiotropy+++/+++1

Bivariate analysis with liability to thrombosis Chromosome 10 – no improvement in likelihood Chromosome 5 – h2q for liability > 0, p = Inference: The FXII QTL on chromosome 5 also influences susceptibility to thrombosis.

Summary Two QTLs on chromosomes 5 and 10 influence FXII levels. The QTL on chromosome 5 also influences liability to thrombosis and is likely to be the FXII structural gene. FXII 46C/T appears to functionally influence FXII levels, but our results suggest additional functional variants exist in or near FXII.