复旦大学：《医学遗传学 Medical Genetics》课程教学资源（PPT课件讲稿）Complex disorders

Medical genetics Complex disorders Lecturer: David Saffen Ph. D Laboratory for molecular neuropsychiatric Genetics Department of cellular and genetic Medicine School of Medicine, Fudan University saffen@fudan.edu.cn

Medical Genetics: Complex disorders Lecturer: David Saffen. Ph.D. Laboratory for Molecular Neuropsychiatric Genetics Department of Cellular and Genetic Medicine School of Medicine, Fudan University saffen@fudan.edu.cn

Outline A Historical background B Phenotypes in populations C Genes in populations D Mapping disease genes E Complex disorders

Outline A. Historical background B. Phenotypes in populations C.Genes in populations D.Mapping disease genes E. Complex disorders

A. Historical background · Francis Galton: normal distributions of quantitative traits Ronald A. fisher polygenic models for quantitative traits

A. Historical background • Francis Galton: normal distributions of quantitative traits • Ronald A. Fisher: polygenic models for quantitative traits

Biometrics and Mendelian genetics Francis Galton was a pioneer in using statistica methods to quantify human traits and behaviors For example he recognized that the distribution of many traits such as height, weight, intelligence closely approximate the"noma”( aka Gaussian”) distribution He also recognized that inherited traits tended to move toward average values, a phenomenon he termed, " regression to the mean Most of galton s work on inheritance was carried out before the re-discovery of Mendel's experiments Sir Francis Galton 1822-1911 The paradigm under which Galton and other (English Victorian polymath;"biometricians"worked was that inheritance of human Cousin of charles darwin traits involved the mixing or blending of factors present biometician; eugenicist) in the parents. This picture is very different from that obtained from Mendel's experiments, which implied that inherited traits are determined by discrete factors that remain unchanged from generation to generation

Biometrics and Mendelian genetics Sir Francis Galton 1822-1911 (English Victorian polymath; Cousin of Charles Darwin; biometician; eugenicist) Francis Galton was a pioneer in using statistical methods to quantify human traits and behaviors. For example, he recognized that the distribution of many traits such as height, weight, intelligence closely approximate the “normal” (aka “Gaussian”) distribution. He also recognized that inherited traits tended to move toward average values, a phenomenon he termed, “regression to the mean.” Most of Galton’s work on inheritance was carried out before the re-discovery of Mendel’s experiments. The paradigm under which Galton and other “biometricians” worked was that inheritance of human traits involved the mixing or blending of factors present in the parents. This picture is very different from that obtained from Mendel’s experiments, which implied that inherited traits are determined by discrete factors that remain unchanged from generation to generation

Normal distributions of quantitative traits and regression to the mean Mean E5E6E Mean height 2 SD below 2 SD above the meat the mean Stature(inches) SD= standard deviation

Normal distributions of quantitative traits and “regression to the mean” Mean height 45° slope SD = standard deviation

Unification of biometrics and mendelian genetics RA Fisher was a 20th century genius who made fundamental contributions to the fields of statistics and biology. In statistics, he developed analysis of variance(ANOVA), the maximum likelihood method for estimating the values of parameters based on experimental data, permutation testing to estimate statistical significance(P-values), and exact tests for estimating statistical significance in small samples In biology, Fisher(together with Sewall Wright and Sir Ronald A Fisher(1890-1962) J.B.S. Haldane) is considered one of the founders English statistician, evolutionary of the "Modern Evolutionary Synthesis, " which unified biologist, geneticist, eugenicist; Darwin s theory of natural selection with mendel- Published: The correlation Between relatives on the inspired concepts of modern genetics. Among many supposition of Mendelian contributions, Fisher was the first to propose the idea Inheritance”in1918 of heterozygote advantage to explain the persistence of harmful genetic variants in certain populations

Unification of biometrics and Mendelian genetics Sir Ronald A. Fisher (1890-1962) English statistician, evolutionary biologist, geneticist, eugenicist; Published: “The correlation Between relatives on the supposition of Mendelian Inheritance” in 1918. RA Fisher was a 20th century genius who made fundamental contributions to the fields of statistics and biology. In statistics, he developed analysis of variance (ANOVA), the maximum likelihood method for estimating the values of parameters based on experimental data, permutation testing to estimate statistical significance (P-values), and exact tests for estimating statistical significance in small samples. In biology, Fisher (together with Sewall Wright and J.B.S. Haldane) is considered one of the founders of the “Modern Evolutionary Synthesis,” which unified Darwin’s theory of natural selection with Mendel￾inspired concepts of modern genetics. Among many contributions, Fisher was the first to propose the idea of heterozygote advantage to explain the persistence of harmful genetic variants in certain populations

The combined effects of multiple genes can produce normal distributions for quantitative traits (A)one locus (C) three loci AABbcC AAbbCc AAbbcc AaBBcc aaBBCC AaBbcc aaBBCc AAbbCc AabbCc AabbCC AABBcc aaBBcc aaBbCC AaBbCC a BbCc AaBbCc AaBBCc Aabbcc aabbcc AABbCC AABBCc aaBbcc AAbbCc aaDo AaBBCC aabbcc AABBCC 708090100110120130 708090100110120130 (B)two loci (D) many loci 8 aab 708090100110120130 708090100110120130

The combined effects of multiple genes can produce normal distributions for quantitative traits

B. Phenotypes in populations Familial aggregation of disease Disease risk as a quantitative trait Factors that obscure patterns of inheritance

B. Phenotypes in populations • Familial aggregation of disease • Disease risk as a quantitative trait • Factors that obscure patterns of inheritance

Familial aggregation of disease Relative risk Prevalence of the disease among the relatives of an affected person Prevalence of the disease in the general population Concordance and allele sharing among relatives Genotype of sib #1 A1A4 A2A3 A2A4 AlA2 Degree of Relationship and Alleles in Common AlA3 Proportion of Alleles in A1 Relationship to proband Common with Proband M A2A3 First-degree relative 12 Second-degree relative A2A40 Third-degree relative 1/8 0. 25 (2 shared alleles)+0.5(1 shared allele +0.25 (0 shared alleles)=1 shared allele (average). One-of-two alleles shared 50% shared alleles

Familial aggregation of disease • Relative risk • Concordance and allele sharing among relatives Prevalence of the disease among the relatives of an affected person Prevalence of the disease in the general population lr = 0.25 (2 shared alleles) + 0.5 (1 shared allele) + 0.25 (0 shared alleles) = 1 shared allele (average). One-of-two alleles shared = 50% shared alleles

Correlations between risk of developing schizophrenia and the degree of relatedness among relatives GENES SHARED eral popul 125%(1/8) first cousins 3rd degree relatives uncles/aunts nephews/ nieces ■25%(1/4 2nd degree relatives grandchildren half siblings 50%(1/2) nst degree relatives arents children fraternal twi identical twins 10 RELATIONSHIP TO PERSON RISK OF DEVELOPING SCHIZOPHRENIA WITH SCHIZOPHRENIA

(1/2) (1/4) (1/8) Correlations between risk of developing schizophrenia and the degree of relatedness among relatives