常见多基因疾病的遗传咨询

λS – IDDM – NIDDM
λ1 – Schizophrenia – Autism
10-15 4
10 ~100
Diabetes Mellitus
Maturity onset diabetes of the young (MODY)
Association and Linkage
ASSOCIATION of a specific allele at a genetic locus with disease in a population – Candidate gene LINKAGE. Co-segregation in families of a marker locus, regardless of specific allele, with disease.
Background
Complex Common Diseases
Central Points
Polygenic traits controlled by two or more genes Multifactorial traits are polygenic with an environmental component Many other multifactorial traits
Predictions from Threshold Model
Recurrence risks are average Risk increases with # of affected relatives Risk increases with severity of malformation Differential risk increases as frequency decreases Sex differences
Background
Human Genome Project &Post-Genome Era
Human Genome Project
February 2010 marked the 10th anniversary of the completion of the human genome project
Initial sequence was finished early because of advancements in genome sequence technology
Resulted in drastically reduced labor & delivery costs
Human Genome Sequencing Costs
常见多基因疾病的遗传咨询
Outline
Background
--Complex Common Diseases --Human Genome Project &Post-Genome Era
Genetic Counseling for Common Disease Age-related macular degeneration (AMD) Type 2 diabetes mellitus (T2DM) Essential hypertension (EH) Alzheimer disease (AD) Parkinson’s disease (PD)
2000 – Human Genome Project – $3 billion 2007 – James Watson – $2 million 2009 – Illumina & Helicos – $50,000 2010 – Illumina HiSeq – $10,000 2014 – Multiple companies – $1,000
pancreatic β-cell or insulin action
• ABCC8 (sulphonylurea receptor), INS, INSR, etc.
PLOS Bio 2003;来自百度文库:41
Alternative Approach
Genome-wide association studies (GWAS) – Hypothesis: common genetic variants (>5%) ; common
Candidate Gene Approach
Are there potential candidate genes? – Genes that are selected based on known biological,
physiological, or functional relevance to the phenotype under investigation
Evidence for Genetic Factors in Common Complex Diseases
Familial aggregation Twin studies Mendelian forms of disease
Familial Aggregation
Increased risk to relatives: λR
Complex Disease Genetics
other genes genotype
phenotype1 phenotype2 phenotype3 phenotype4
disease state phenotype5
environment
J Intern Med 2008;263:16
Threshold Model
diseases (traits)
– Approach is limited by its reliance on existing knowledge
about the biology of disease
– Associations may be population-specific E.g., type 2 diabetes – Genes encoding molecules known to primarily influence