L10, Hereditary aspects of human longevity

Question 1

Evidence for hereditary origin of extreme longevity (Cent.):

Answer 1

• Sibling of centenarians born in 1900 are 8 (F) to 17 (M) times more likely to live to near 100 compared with the rest of their birth cohort

Question 2

Heritability vs heredity:

Answer 2

• Heredity encompasses everything you inherit from parents; genetic, environmental aspects, including epigenetics and microbiome composition
• Heritability primarily refers to host genetics
• Heritability = proportion of variation in phenotype explained by genetics; quantitative concept

Question 3

Phenotypic variation:

Equation and definition

Answer 3

• V^P = V^G + V^E
• … genetic variation + variation due to the environment

Question 4

What percentage of longevity variation is explained by genetics? Effect of increasing age on these estimates?

Features of study?

Answer 4

• Using data from monozygotic (MZ) and dizygotic (DZ) twins, heritability for longevity was estimated at 25-30%
• Much of this estimate is for ages >60, and much is contributed by families that cluster for longevity
• Big issue of bias due to incomplete data
• Estimate of genetic contribution to longevity increases with age
• -> Falconer’s formula
• H^2 = 2x (r MZ - r DZ)
• Where r = Pearson correlation coefficient

Question 5

Estimate of genetic contribution to longevity increases with age: Why is it so high?

Answer 5

• Increasingly homogenous environment with less variance
• Genetic influences/differences may be being expressed later in life

Question 6

Evidence against environment/lifestyle as the cause of exceptional longevity:

Answer 6

• People with exceptional longevity are not distinct in terms of lifestyle factors from the general population -> may be interacting with environmental factors differently
• e.g. Ashkenazi Jews: 60% of their centenarian population are heavy smokers and 50% have been obese for most of their lives. Less than half do even moderate exercise, <3% vegetarian -> half the CD prevalence of their peers with equivalent lifestyles

Question 7

Principle of GWAS:

Answer 7

• Genome-wide association studies, identifying SNPs
• SNPs: Linkage with the locus responsible for affecting phenotype
• Able to compare proportion of particular SNP variants between test and control cohorts
• Likely an underestimate due to choice of significance level

Question 8

Population-based GWAS studies:

Answer 8

• Cross sectional
• e.g. New England Centenarian study, German long-lived individuals
• Using long-lived vs control cohort born at the time

Question 9

Family-based GWAS cohort studies:

Answer 9

• e.g. Ashkenazi Jews, Genetics of healthy aging (GEHA) study, LLS
• Often use offspring as study group and offspring partners or unrelated matched group as controls

Question 10

Prospective GWAS studies:

Answer 10

• e.g. Lieden 85-plus study, Framingham heart study etc
• Nearly all use case/control e.g. centenarians

Question 11

SNPs associated with exceptional longevity:

Answer 11

• APOE often stands out
• WRN: Associated with Werner syndrome
• CDKN2A/B

Question 12

What is APOE?

Answer 12

• Apolipoprotein E
• Present for development and growth
• Locus associated with lifespan, CVD and AD risk
• Probably a frailty gene rather than longevity gene
• E3 most frequent
• E4 known to be harmful

Question 13

Long life is not due to fewer disease alleles: Discuss

Answer 13

• GWAS studied SNPs for risk of CD, cancer and type II diabetes in long-lived vs controls
• No difference in total risk alleles observed
• It is, however, possible that some rare longevity alleles are being overlooked
• Disease alleles still frequent in long-lived populations may signify positive selection via antagonistic pleiotropy

Question 14

Earlier results of GWAS for longevity in humans:

Answer 14

• Early longevity GWAS identified 3 loci: APOE, FOXOA3, rs2149954
• Other two explained less than 2% of lifespan variance
• Suggestive that longevity loci are deleterious i.e. the minor allele is associated with a reduced lifespan
• Small effect sizes

Question 15

Examples of protective alleles found in GWAS studies:

Answer 15

• Rare alleles promoting longevity -> alleles for USP42, ELOVL6, MHC
• Possible links to cancer and inflammaging
• Other Ashkenazi Jew study: variants in IIS, AMPK and Wnt signalling -> however, may be compensatory mechanisms to rare deleterious alleles (such as APOE4) which made them stand out

Question 16

Dose effect in New England study:

Answer 16

• Found that numerous minor alleles of small effect could be additive towards better lifespans
• Dose effect for SNPs