8.2. Examples of complex disease

What are the two main subtypes a patient may develop after a first psychotic episode?

Affective psychosis disorders (AP): psychotic bipolar disorder, psychotic major depressive disorder; Non-affective psychosis disorders (NAP): schizophrenia, schizoaffective disorder

How can polygenic risk scores (PRS) improve outcomes after a first psychotic episode?

If PRS can predict which subtype a patient will develop, early intervention can be improved and management tailored accordingly

What is the lifetime risk of breast cancer for women in the UK?

1 in 7

What characterises the subset of breast cancer cases with a strong genetic component?

Strong family history and early onset before age 45

What are BRCA1 and BRCA2?

Major susceptibility genes for breast and ovarian cancer, accounting for 20-25% of familial risk

What is the breast cancer risk for BRCA1+ women?

65-85 out of every 100 BRCA1+ women will develop breast cancer

What is the ovarian cancer risk for BRCA1+ women?

40-63 out of every 100 BRCA1+ women will develop ovarian cancer

What is the breast cancer risk for BRCA2+ women?

40-85 out of every 100 BRCA2+ women will develop breast cancer

What is the ovarian cancer risk for BRCA2+ women?

10-27 out of every 100 BRCA2+ women will develop ovarian cancer

What are the risk management options for BRCA1/2+ individuals?

Lifestyle changes (reduce weight, reduce alcohol, come off contraceptive pill), screening (yearly breast screening, self-screening), chemoprevention (e.g. tamoxifen), and surgery (mastectomy)

What are examples of complex diseases?

Hypertension, type 2 diabetes, cardiovascular disease, schizophrenia, Parkinson's disease, Alzheimer's disease, and rheumatoid arthritis

What is an example of a dichotomous complex disease with polygenic liability?

Cleft palate — diagnosis is dichotomous (present or absent) but fusion is governed by multiple genetic and environmental factors from 7 weeks of embryonic development

What does it mean that liability in cleft palate is polygenic and continuous?

It follows a normal distribution, allowing comparison of affected numbers across different populations to determine different levels of risk

What type of trait is type 2 diabetes and what is known about its genetics?

An adult-onset binary threshold trait with no single causative gene identified — multiple associated genes increase susceptibility alongside environmental factors

What do genes determine in type 2 diabetes?

Risk, not cause

What evidence supports a genetic component in schizophrenia?

People who share more DNA are more likely to share the phenotype — schizophrenia is more prevalent among family members than the general population, expressed as a familial risk ratio

What are the caveats of adoption studies for schizophrenia?

They require good information on biological family, risk of selective placement in environments similar to the biological family, and shared intrauterine environment

What is personalised medicine in the context of complex disease?

Improving patient treatments by recognising and targeting genetic subtypes

What side effect can clozapine cause in schizophrenia treatment?

Agranulocytosis

What genetic variant is associated with clozapine-induced agranulocytosis?

Variants in the HLA locus

What side effect can levodopa cause in Parkinson's treatment?

Dyskinesias

What does PRS show regarding levodopa-induced dyskinesias in Parkinson's?

PRS is associated with increased risk with an odds ratio of 1.2; women had a higher ratio of 1.8, suggesting bigger contributing factors

What is the caveat of using PRS in schizophrenia personalised medicine?

Risk is polygenic — no single variant explains the risk