Human Linkage Studies of Psychiatric Illness

Extreme Discordant And Concordant Sib Pair Design

Both Siblings in Top 10% Both Siblings in Bottom 10%One Sibling in Top and one in Bottom 10%

Risch and Zhang, Science, 268:1584, 1995

Neuroticism

Neuroticism(N)

• N is a strong predictor of the onset of depression

Neuroticism(N)

• N is a strong predictor of the onset of depression

• N is subject to genetic effects that are shared with depression

E.P.Q (Adult)

INSTRUCTIONS Please answer each question by putting a circle around the “YES!” or the “NO” following the question. There are no right or wrong answers and no trick questions. Work quickly and do not think too long about the exact meaning of the questions.

PLEASE REMEMBER TO ANSWER EACH QUESTION 1 Do you have many different hobbies? YES NO 2 Do you stop to think things over before doing anything? YES NO 3 Does your mood often go up and down? YES NO 4 Have you ever taken the praise for something you knew

someone else had really done? YES NO 5 Are you a talkative person? YES NO 6 Would being in debt worry you? YES NO 7 Do you feel “just miserable” for no reason? YES NO 8 Were you ever greedy by helping yourself to more than

your share of anything? YES NO 9 Do you lock up your house carefully at night? YES NO 10 Are you rather lively? YES NO 11 Would it upset you a lot to see a child or an animal suffer? YES NO 12 Do you often worry about things you should have

done or said? YES NO

14 Are your feelings easily hurt? YES NO 15 Are all your habits good and desirable ones? YES NO 16 Do you tend to keep in the background on social occasions? YES NO 17 Would you take drugs which may have strange or

dangerous effects? YES NO 18 Do you often feel “fed-up”? YES NO 19 Have you ever taken anything (even a pin or button)

that belonged to someone else? YES NO 20 Do you like going out a lot? YES NO 21 Do you enjoy hurting people you love? YES NO 22 Are you often troubled by feelings of guilt? YES NO

Sex Name E L N Pf 1 4 1 19 4f 2 17 3 18 0f 3 6 10 17 0f 4 9 8 16 6f 5 5 6 16 0f 6 17 3 16 3f 7 15 5 14 2f 8 17 4 9 4f 9 7 15 9 2f 10 7 8 8 5f 11 18 2 7 6f 12 13 6 5 3m 1 2 13 14 0m 2 7 6 10 4m 3 12 4 8 8m 4 10 4 5 0m 5 14 5 3 10m 6 12 2 10 3m 7 18 7 4 2

Female 11.25 5.92 12.83 2.92Male 10.71 5.86 7.71 3.86

Vicissitudes of Large Scale Studies

Address Labels

Dr Jonathan Flint

University of Oxford

PO BOX 321

Rotherham

Yorkshire

Dear Sirs STRESS QUESTIONNAIRE My doctors have sent me one of your questionnaires. The questions in it are so banal that I will not answer them or return it. I am perplexed that a reputable research institution could expect people to answer such complex questions like these with simple yes/no answers. Anyone with a basic understanding of human nature must realise that people who reply are clearly not worth asking. Have you thought of finding out if the tendency to own colour televisions is inherited? I have evidence that it is? Or have I missed the point? Are you really trying to find out if people are prepared to waste their time:

Filling in questionnaires Or

Writing letters? I am pleased to report that a number of my work colleagues have also received copies of the questionnaire and that they have either consigned them to the rubbish bin or returned them with random and fictitious answers. I am amazed that you have the gall to waste money (no doubt not your own) on this fatally flawed exercise Yours faithfully,

EPQ Responses

Siblings

Female 52,249

Female 16,186

Male 35,892

Male 10,613

TOTAL 88,141

SIBLING PAIRS: 34,000

-3.00000 -1.00000 1.00000 3.00000

Standardized Residual

0

2000

4000

6000

Co

un

t

Total Sample

The Neurotic Family Receives a DNA Swab Request From Dr

Flint

“ I have just received your request to send a mouth swab. This is the last straw. My holiday has just been cancelled, my son has influenza and my husband has left me. Now this from you! It is the END!”

-2.00 -1.00 0.00 1.00 2.00

Standardised Residual N-Score

0

50

100

150

Co

un

t

Selected Sample

Mapping Results

• Complete genome scan (LMS2 marker set: 396 markers)

• 500 families

How To Analyze The Data

Regression analysis

• Use information from squared differences and sums of sibling phenotypes (Visscher and

Hopper Ann Hum Genet 65:583)

Regression analysis

Sib 1 Sib 2Squared

SumSquared

Difference IBD20 20 1600 0 11 1 4 0 120 1 441 361 010 10 400 0 0.5

Visscher-Hopper Regression

0

1

2

3

4

5

0 500 1000 1500 2000 2500 3000

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

LogP

Distance (cM)

Genome-wide significance thresholds

• Simulate 10,000 data sets with the same allele frequencies, linkage, missing data, and family structure

(SIMULATE – Terwilliger, Genet Epidem 10:217, 1993 and MERLIN – Abecasis, Nat Genet 30:97, 2002)

Genome-wide significance thresholds

• Five percent threshold: 3.8

• One percent threshold: 4.7

Visscher-Hopper Regression

0

1

2

3

4

5

0 500 1000 1500 2000 2500 3000

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

LogP

Distance (cM)

Gender Effects

Sex Name E L N Pf 1 4 1 19 4f 2 17 3 18 0f 3 6 10 17 0f 4 9 8 16 6f 5 5 6 16 0f 6 17 3 16 3f 7 15 5 14 2f 8 17 4 9 4f 9 7 15 9 2f 10 7 8 8 5f 11 18 2 7 6f 12 13 6 5 3m 1 2 13 14 0m 2 7 6 10 4m 3 12 4 8 8m 4 10 4 5 0m 5 14 5 3 10m 6 12 2 10 3m 7 18 7 4 2

Female 11.25 5.92 12.83 2.92Male 10.71 5.86 7.71 3.86

Gender Effects

Gender Heritability of NMales 0.49Females 0.41

Sex specific heritability of N

Type of Pair Correlation in N scoreMale 0.181Female 0.186Male-Female 0.157

Male and Female Pairs

Female PairsMale Pairs

0

1

2

3

4

5

0 500 1000 1500 2000 2500 3000

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

QTL on Mouse Chromosome One

(Fearfulness)

0

5

10

15

20

25

30

0 20 40 60 80 100

Mouse Human Homology

Human 1q

Rat Fearfulness

0

1

2

3

4

5

6

7

8

9

10

0 20 40 60 80 100 120 140

Rat Chromosome 5

01237

119 RNO5 HSA9 9q22.3-q31119 RNO5 HSA9 9q32156185223260286 RNO5308 RNO5 HSA1 1p31323 *359 *385 *394 RNO5 HSA1 chr.1426 *

443 RNO5 HSA1 1p35-p31.3

443 RNO5 HSA1 1p35-p34458 *470 *497 *

514 RNO5 HSA1 1p36-q12520 *556 RNO5 HSA1 1p33

596 RNO5 HSA1 1p36.2-p35

596 RNO5 HSA1 1p36.1-1p34.3

620 RNO5 HSA1 1p36.1-p35630 RNO5 HSA1 1p36.1

630 RNO5 HSA1 1p35-p34

639 RNO5 HSA1 1p36.3-34.4652 RNO5 HSA1 1p35666 *682 *694 *717 *746 RNO5 HSA1 1p36.2794 RNO5 HSA1 1p36.2818 RNO5 HSA1 1p36.3840 RNO5 HSA1 1p36.3859 *

881 RNO5 HSA1 1p36.3-p32

HUMANChr

(HSA)RAT cRay

Rat Human

Human 1p

Synteny?

0

1

2

3

4

5

25 75 125 175 225 275

Distance (cM)

Ne

ga

tiv

e L

og

P

Rat Mouse

Summary

• Genetic effects on neuroticism can be found using an extreme discordant and concordant pair design

• Loci on chromosomes 1, 4, 7, 8, 11 and 12

• Sex specific effects• Syntenic with rodent loci