POPH90111 Genetic Epidemiology

Question 1

As a genetic epidemiologist, you decide to conduct a genome-wide association study for a disease called Machotic disease. The study includes 2,000 people with Machotic disease (cases) and 2,000 people without Machotic disease (controls). The cases and controls are frequency matched for age, sex and ethnicity i.e., the cases, on average, are the same age, have the same proportion of each sex, and the same proportion of ethnicities as the controls. You obtain the following genotype results of 3 of the 500,000 SNPs tested.

SNP and genotype	Number of Cases	Number of Controls
rs191 GG	1100	1210
GA	780	690
AA	120	100
rs192
TT	1440	1406
TC	488	532
CC	72	62
rs193
CC	1160	1144
AC	712	746
AA	128	110

Case

Gregor’s disease is a rare disease resulting in patches of green wrinkly skin. One of the suspected causes for Gregor’s disease is a bacteria found in the soil of garden beds, because previous studies have shown that vegetable growers are more likely to develop the disease. However, other theories have been proposed for this association including confounding with pesticides.

As a genetic epidemiologist, your aim is to determine whether soil bacteria is actually a likely cause of Gregor’s disease. You decide to use Mendelian Randomisation to address this aim. You begin by conducting a case-control study by recruiting 2,000 people with Gregor’s disease (cases) and 2,000 people without Gregor’s disease (controls) and ask them to complete a questionnaire on their lifetime exposure to garden soil and pesticides. You also collect a DNA sample from the cases and control via a cheek swab and you genotype the cases and controls for the C allele of the SNP rs2019, which has been previously shown to make the carrier susceptible to any bacterial infection. The evidence to support this comes from a large previous study, which showed 15% of those with a C allele of the SNP rs2019 had a bacterial infection in the past year compared with 1% of those without a C allele.

You obtain the following results:

1) 40% of the cases (who have Gregor’s disease) and 25% of the controls (who do not have Gregor’s disease) have at least one C allele of the SNP rs2019.

2) Of those with at least one C allele of the SNP rs2019, 10% reported using pesticides once a year or more compared with 11% of those without a C allele.
ANSWER THE FOLLOWING QUESTIONS.

Oscurophobia is a psychiatric disorder that rarely occurs in humans. People with Oscurophobia experience panic attacks when suddenly exposed to anything dark. Even wearing black or dark coloured clothes or looking into the dark spaces, results in high levels of anxiety. The causes of Oscurophobia are not well known but a proportion of the disease is known to be caused by an inherited mutation in the gene OS13. To date, only one inherited mutation has been identified in this gene: a substitution of a C for a T at base 2019 that results in an early stop codon. Approximately 0.2% of the population carry the T allele in OS13 (i.e., approx. 1 in 500 people carry one mutated allele) and they have an increased risk of Oscurophobia. The two penetrance studies conducted to date have reported different estimates of penetrance.

STUDY 1. People with a family history of Oscurophobia (probands) were recruited from a genetics clinic and tested for the T variant in OS13. If the proband was found to carry the T variant, then all known relatives were invited to participate in the study and were tested for the T variant. A survival analysis of carriers of the T variant (including the probands) was conducted. Carriers of the T variant had a cumulative risk to age 70 years of Oscurophobia of 65% (95% confidence interval, 52% to 76%).

STUDY 2. Recently diagnosed cases of Oscurophobia (probands) were recruited irrespective of having a family history and tested for the T variant in OS13. If the the proband was found to carry the T variant, their first- and second-degree relatives were then invited to participate in the study and were tested for the T variant. A modified segregation analysis of the relatives but excluding the probands was conducted. Carriers of the T variant had a cumulative risk to age 70 years of Oscurophobia of 30% (95% confidence interval, 21% to 42%).

Estomagosis is a gastrointestinal disorder resulting in frequent abdominal pain, discomfort and constipation. The disease’s causes are not well known but a proportion of the disease is known to be caused by an inherited mutation in the gene AK19. Some studies reported smoking and fruit intake are also associated with Estomagosis. As a genetic epidemiologist, you decide to conduct a case-control study to investigate gene and environmental interactions associated with Estomagosis. The study includes 400 people with Estomagosis (cases) and 390 people without Estomagosis (controls). You genotype AK19 mutation in both cases and controls and survey them for long-term smoking, and if they regularly take fruits. You obtain the following results. 

AK19 mutation	Long-term smoker	Estomagosis Present	Estomagosis Absent
No	No	280	320
No	Yes	30	20
Yes	No	60	40
Yes	Yes	30	10

 

AK19 mutation	Regular fruit intake	Estomagosis Present	Estomagosis Absent
No	No	295	300
No	Yes	15	40
Yes	No	58	34
Yes	Yes	32	16