203.343!GWAS – the Issue of

Missing Heritability!Week 5!

Austen Ganley, August 10th, 2015

Penetrance – complete vs incomplete penetrance

•  Penetrance is the proportion of individuals that carry a disease (trait) mutation that have that disease (trait)!

!•  Complete penetrance: all who have the mutation

have the disease/trait!•  Incomplete penetrance: not all who have the

mutation have the disease/trait!

•  Most genetic diseases are incompletely penetrant!

Incomplete Penetrance

vs Variable Expressivity

Incomplete Penetrance

Incomplete penetrance: classic example - phenylketonuria

•  Phenylketonuria is caused by a mutation in the phenylalanine hydroxylase (PAH) gene!

•  The failure to metabolise phenylalanine leads to severe intellectual disabilities and other consequences!

•  However, if phenylalanine is strictly limited in the diet, symptoms can virtually be nil!

•  Therefore, phenylketonuria is not completely penetrant, due to dietary differences!

What causes incomplete penetrance?

Cooper et al, 2013 Human Genetics 132: 1077–

For example: age and CJD •  Creutzfeldt-Jakob Disease (CJD) is a prion

disease!•  Results in brain tissue degeneration,

dementia, and rapid death after onset!•  There is an inherited form, caused by a

E200K mutation in a gene called Prp!•  This was thought to have incomplete

penetrance, estimated at 0.56!

For example: age and CJD •  Spudich et al, 1995 (Molecular Medicine 1:

607-) looked at cases in a population with this mutation. They found:!

For example: age and CJD •  Therefore, the

penetrance depends on the age at which you are looking!

•  They plotted this (1-Si is basically penetrance):!

•  Conclude that penetrance is basically complete!

Angelina Jolie and BRCA1 •  About 20 years ago two genes were located

in which mutations result in large-effect breast cancer risks with relatively high penetrance!

•  These are BRCA1 and BRCA2 (breast cancer type 1/2 susceptibility protein genes)!

•  BRCA1 has become famous because Angelina Jolie had a double mastectomy and oophorectomy after finding she had a BRCA1 mutation!

Angelina Jolie and BRCA1 •  She was at a higher risk because of a family

history of breast/ovarian cancer!•  See the two articles she wrote for the New

York Times on this:!•  http://www.nytimes.com/2013/05/14/opinion/my-

medical-choice.html!•  http://www.nytimes.com/2015/03/24/opinion/

angelina-jolie-pitt-diary-of-a-surgery.html!•  Double mastectomy reduces the risk of

developing breast cancer by about 90%!

What does the BRCA1 gene do? •  BRCA1 and BRCA2 are both genes involved

in homologous recombination!•  Homologous recombination, except for its

specalised role in crossing over in meiosis, is a very important DNA repair pathway!

•  Therefore, cancer susceptibility is likely due to some impairment in the process of DNA repair, increasing the rate of mutation that then leads to cancer development!

•  Why does this particularly affect breast tissue?!

BRCA1 and Penetrance •  Women with BRCA1 mutations have a

~60-90% risk of developing breast cancer, and a ~40-60% risk of developing ovarian cancer!

•  The difference in risk reflects things like family history (and thus probably other inherited mutations) and the type of mutation it is!

•  Women overall have a ~12.5% chance of developing breast cancer!

•  Women with a BRCA1 mutation account for about 5% of all diagnosed breast cancers!

GWAS – what does it do?

What is the implicit assumption?

How heritability is calculated •  There are four common ways for estimating

heritability in human populations:!•  Correlation of trait status in pairs of relatives (e.g. if

looking at two siblings, how many pairs either both have it or both don’t)!

•  Mono-zygotic versus di-zygotic twin studies (di-zygotic twins are only 50% related to each other)!

•  Family studies (look to see how many family members are affected after diagnosing an affected individual versus what would be expected)!

•  Mixed linear models (basically the family study approach, but uses sophisticated statistical techniques to incorporate more pedigree information more powerfully than traditional family studies can)!

So, the basic scheme is:

Calculate heritability

for trait/disease of

interest!

Perform GWAS to identify genetic variants

responsible for this

heritability!

Common disease-common variant hypothesis wrong

GWAS: idea was that most diseases result from a moderate number of variants at moderate frequency. Missing heritability shows this is not true!

Why is missing heritability a problem?