Team 1: Negative Psychological Attributes

Team 1: Negative Psychological Attributes

Mirjam Sprangers, Ph.D.Academic Medical Center/University of Amsterdam

Frank Baas, Ph.D. Academic Medical Center/University of Amsterdam

Nick Martin, Ph.D.University of Queensland

Miriam Mosing, M.Sc.University of Queensland

Genetic Disposition & PatientGenetic Disposition & Patient--reported Quality of Life Outcomesreported Quality of Life Outcomes

Rochester, MN, February 26 Rochester, MN, February 26 –– 28, 200928, 2009

Acknowledgements

Prof. dr. Dick SwaabNetherlands Institute for Neuroscience, AMC, University of Amsterdam

Dr. Eric RuhéDepartment of Psychiatry, AMC, University of Amsterdam

Judith van der Harg, Linda Hoogland, Tessa van

der Maaden, Boy Vissers, Nathalie Audureau,

Willemieke Kouwenhoven, Eva NaninckMaster students Neurobiology, University of Amsterdam

Negative Psychological Attributes:

Definition

• Psychological functioning: psychological distress <-> positive sense of

well-being

• Focus of effort: Negative side of this continuum;

"normal" feelings of distress

Negative Psychological Attributes:Biological and genetic research

• Mostly conducted in pathology and psychiatry

• We expect a similar biological substrate for non-

pathological negative affect

• The focus is on major depressive and anxiety disorders

• There is a large variety of depressive and anxiety disorders

• The following summary can therefore only be

sketchy and incomplete

Question 1

Which potential biological pathways have been considered and/or shown to describe a possible genetic disposition for negative

psychological affect?

Question 2

Which genes and genetic variants have been considered and/or shown to have a potential association with negative psychological affect?

The problem of gene finding in relatively The problem of gene finding in relatively frequent diseasesfrequent diseases

•• Is a single mutation responsibleIs a single mutation responsible

•• Usually notUsually not

•• Is a single gene responsibleIs a single gene responsible

•• Probably notProbably not

•• How do we solve this problemHow do we solve this problem

•• Define the phenotypeDefine the phenotype

•• Analyze specific formsAnalyze specific forms

•• Analyze associated conditions Analyze associated conditions ((endophenotypesendophenotypes))

Genes significantly associated to depression in meta-analysis

(López-León et al., Molecular Psychiat 2008; 13: 772-85)

• apolipoprotein E (APOE)• guanine nucleotide-binding protein (GNB3)• methylenetetrahydrofolate reductase (MTHFR)• dopamine transporter (SLC6A3)• SLC6A4

Candidate Genes/Genetic Variants: HPA System

• Mineralocorticoid receptor (MR) / AR / CRHR1• Glucocorticoid receptor (GR) (NR3C1) / ER1,2 / CRHR2• VMAT2• Arginine vasopressin (AVP), AVPR1b/1a• Oxytocin (OXTR)• DA receptors• Opiate receptors• 5HT receptors (5HT2A/1A); 5HT transporter• GABA receptors / Glutamate• CR (cannabis)• BDNF / Trx B• Melatonin receptors• Clock genes (NPAS2, ARNTL, PER3)• Urocortin receptors• NPY receptors• Orexin receptors• Adrenergic receptors (α2 A) • Thyroid hormones, receptors and transporters

Candidate Genes/Genetic Variants: Dopamine and Serotonin

• Dopamine- dopamine transporter (DAT)- Catechol-O-methyltransferase (COMT)

- D4-receptor (DRD4)

• Serotonin- serotonin transporter 5-HTT- Catechol-O-methyltransferase (COMT)

- MAO-A gene

COMT genotype & YCOMT genotype & Y--BOCS scoresBOCS scoresYALEYALE--BROWN OBSESSIVE BROWN OBSESSIVE

COMPULSIVE SCALE in schizophreniaCOMPULSIVE SCALE in schizophrenia

30

20

10

0

COMT genotype

Y-B

OC

S t

ota

l s

co

res

N=12 N=34 N=12

Val/ValN=23

Val/MetN=51

Met/MetN=12

P=0.005

P=0.042 P=0.022

Question 3

What datasets are available to explore the association of genes and negative psychological affect?

Available Australian DataAvailable Australian Data

•• The Australian Twin Registry (ATR) The Australian Twin Registry (ATR) -- a a volunteer register.volunteer register.

•• Data have been collected on a range of Data have been collected on a range of phenotypes (e.g. Alcohol/Drug phenotypes (e.g. Alcohol/Drug consumption, personality etc.) since 1978 consumption, personality etc.) since 1978 (>50,000 individuals)(>50,000 individuals)

•• GWAS data available for almost 10,000 GWAS data available for almost 10,000 adults and 4,000 adolescentsadults and 4,000 adolescents

•• Of the phenotype data how many variables Of the phenotype data how many variables are related to Quality of Life (are related to Quality of Life (QoLQoL) and also ) and also have genotype information available?have genotype information available?

•• Which studies explore phenotypes Which studies explore phenotypes related to related to QoLQoL? ?

•• How many individuals have How many individuals have information available on these information available on these phenotypes of interest?phenotypes of interest?

•• Genotyped?Genotyped?

•• Un/related?Un/related?

OLDER COHORT

(born 1892-1963)YOUNGER COHORT

(born 1964-1971)

Australian Twin Registry

Recruitment Pools

Studies

Mailed Questionnaire

Telephone Interview

In-person Testing or

Measures Taken

relatives ofAlcohol Cohort 1

twins recruited

older twins recruited since

1981

Figure 1. Flowchart of studies that have collected data related to quality of life.

families from Finnish Twin Cohort:selection based on

heavy smokingIndex cases

relatives ofAlcohol Cohort 1

twins recruited

spouses ofSSAGA I

twins recruited

+ sibling recruitment

+ sibling recruitment

13 families with 5 or more

siblings were recruited through other QIMR

studies or themedia

EysenckEysenck Personality Questionnaire Personality Questionnaire (EPQ)(EPQ)

Canberra Study, Canberra Study,

Alcohol Cohort 1 and Alcohol Cohort 1 and

2, Relatives of Alcohol 2, Relatives of Alcohol

Cohort 1 and 2Cohort 1 and 2

PsychoticismPsychoticism ExtraversionExtraversion NeuroticismNeuroticism

(17(17--96 years)96 years) (17(17--96 years)96 years) (17(17--96 years)96 years)

All All phenotypedphenotyped All All phenotypedphenotyped All All phenotypedphenotyped All All phenotypedphenotyped All All phenotypedphenotyped All All phenotypedphenotyped

individualsindividuals and genotypedand genotyped individualsindividuals and genotypedand genotyped individualsindividuals and genotypedand genotyped

Total # fully answeredTotal # fully answered2142121421 41604160 2087620876 40974097 2163921639 42154215

TOTAL # TOTAL # phenotypedphenotyped 2257022570 43334333 2243922439 43214321 2254822548 43324332

Fully answered (founders)Fully answered (founders) 92839283 24752475 90909090 24642464 98769876 24932493

Fully answered (families)Fully answered (families) 59865986 23242324 59655965 22862286 65296529 23352335

PhenotypedPhenotyped (families)(families) 60526052 24262426 60456045 24222422 65936593 24262426

PhenotypedPhenotyped MZ twinsMZ twins 17961796 877877 26582658 875875 28922892 881881

…….. if phenotypes shared.. if phenotypes shared 26582658 895895 26522652 898898 28922892 903903

FemalesFemales 1304913049 28672867 1296612966 28632863 1302813028 28682868

MalesMales 95209520 14661466 94729472 14581458 95199519 14641464

TriTri--dimensional Personality dimensional Personality Questionnaire (TPQ)Questionnaire (TPQ)

Alcohol Cohort 1 and Alcohol Cohort 1 and

2, Relatives of Alcohol 2, Relatives of Alcohol

Cohort 1 and 2,Cohort 1 and 2,

1717--69 years of age69 years of age

Harm Avoidance Harm Avoidance Novelty SeekingNovelty Seeking Reward DependenceReward Dependence

All All phenotypedphenotyped All All phenotypedphenotyped All All phenotypedphenotyped All All phenotypedphenotyped All All phenotypedphenotyped All All phenotypedphenotyped

individualsindividuals and genotypedand genotyped individualsindividuals and genotypedand genotyped individualsindividuals and genotypedand genotyped

Total # fully answeredTotal # fully answered1890718907 38623862 1859718597 37903790 1879218792 38303830

# answered 75# answered 75--99% Q's99% Q's16181618 305305 19191919 370370 17001700 329329

TOTAL # TOTAL # phenotypedphenotyped 2052520525 41674167 2051620516 41604160 2049220492 41594159

Fully answered (founders)Fully answered (founders) 85128512 23132313 84458445 22802280 84938493 23062306

Fully answered (families)Fully answered (families) 53565356 22252225 53065306 21932193 53295329 22242224

PhenotypedPhenotyped (families)(families) 54435443 23352335 54455445 23302330 54465446 23312331

PhenotypedPhenotyped MZ twinsMZ twins 23432343 802802 23072307 794794 23332333 807807

…….. if phenotypes shared.. if phenotypes shared 23432343 870870 23072307 863863 23332333 865865

FemalesFemales 1185011850 27722772 1184811848 27712771 1182311823 27672767

MalesMales 86748674 13951395 86678667 13891389 86688668 13921392

General Health Questionnaire General Health Questionnaire (GHQ)(GHQ)

Over 50Over 50’’s and SSAGA s and SSAGA

Blood StudyBlood Study(31(31--99 years)99 years)

NN females/males females/males

Total # Total # phenotypedphenotyped individualsindividuals 37693769 2539/12302539/1230

Total # genotyped individualsTotal # genotyped individuals 822822 616/206616/206

Total # unrelated individualsTotal # unrelated individuals 692692 NANA

Life Orientation Test Life Orientation Test (LOT)(LOT)

Over 50Over 50’’s studys study

(50(50--94 years)94 years)

NN females/malesfemales/males




Obsessive Compulsive Disorder Obsessive Compulsive Disorder (OCD)(OCD)

Anxiety StudyAnxiety Study

(19(19--95 years)95 years)

All All phenotypedphenotyped All All phenotypedphenotyped

individualsindividuals and genotypedand genotyped

UnaffectedUnaffected 13711371 490490

AffectedAffected 114114 6666

TOTAL # TOTAL # phenotypedphenotyped 14851485 556556

# # phenotypedphenotyped foundersfounders 191191 150150

# # phenotypedphenotyped familiesfamilies 866866 387387

PhenotypedPhenotyped MZ twinsMZ twins 177177 6969

…….. if phenotypes shared.. if phenotypes shared 177177 6969

FemalesFemales 914914 359359

MalesMales 571571 197197

DepressionDepression

Anxiety and NAG/IRPG studiesAnxiety and NAG/IRPG studies

(19(19--95 years)95 years)











MalesMales 17871787 708708

Any Anxiety DisorderAny Anxiety Disorder

Anxiety and NAG/IRPG studiesAnxiety and NAG/IRPG studies

(19(19--95 years)95 years)











MalesMales 26432643 780780

Social PhobiaSocial Phobia

Anxiety Study and SSAGA1Anxiety Study and SSAGA1

(19(19--95 years)95 years)











MalesMales 25022502 709709

Panic or AgoraphobiaPanic or Agoraphobia

Anxiety Study, SSAGA1, Twin 89Anxiety Study, SSAGA1, Twin 89

(19(19--95 years)95 years)











MalesMales 51745174 13001300

How many days during the last year How many days during the last year has illness kept you away from your has illness kept you away from your

normal work?normal work?

Canberra Study, SSAGA1, Canberra Study, SSAGA1,

Alcohol Cohort 1 and 2, Alcohol Cohort 1 and 2,

Relatives of Alcohol Relatives of Alcohol

Cohort 1 and 2Cohort 1 and 2

(17(17--96 years)96 years)

NN females/malesfemales/males




How would you rate your health at How would you rate your health at present?present?

How would you rate your How would you rate your emotional wellbeing at present?emotional wellbeing at present?

Data can be contributed Data can be contributed

Can be increased (Can be increased (phenotypingphenotyping vs. vs. genotyping)genotyping)

Other Existing Datasets:

General Population

• Framingham Sleep Heart Health Study - N = 2772; - Negative affect: SF-36 items (4 items of mental health scale)- GWAs- Open access via dbGAP web portal - Request on behalf of the Consortium submitted

• Framingham Share- N = 3000 (Offspring of above study) - Negative affect: SF-36 items (4 items of mental health scale)- GWAs

Other Existing Datasets:

Disease Populations

• GAIN Major Depressive Disorder StudyNetherlands Twin Register (NTR) and Netherlands Study ofDepression and Anxiety (NESDA) biobanks- Co-Principal Investigator: Dorret Boomsma- N = 1821 MDD cases and N = 1822 controls- range of questionnaires- GWAs available- Open access via dbGAP web portal

Future Datasets

• General population

- LIFEGENE: Swedish general population, N = 500,000

Co-Principal Investigator: Nancy Pedersen

Negative affect: CES-D

Collection of blood

• Disease populations- Breast and prostate cancer: N = 10,000s Swedish patients

Co-Principal investigator: Per Hall- Congenital heart disease: N = 1,400 Dutch patients

Co-Principal investigator: Mirjam Sprangers

Question 4

How would you design a new prospective study to explore the association of genes and negative psychological affect?

New Prospective StudyOperationalization of negative psychological affect

A) Anxiety/depression subdomains or individual items of generic quality-of-life questionnaires, e.g.:


A)Anxiety/depression subdomains or individual items of generic quality-of-life questionnaires, e.g.:

• SF-36 Health Survey (SF-36; SF-12)

• Euroqol EQ-5D (EQ-5D)

• Nottingham Health Profile (NHP)

• Psychological General Wellbeing Index (PGWI)

• Affect Balance Scale (ABS)


B) Anxiety and depression questionnaires, e.g.:


B) Anxiety and depression questionnaires, e.g.:

• Hospital Anxiety Depression Scale (HADS)

• Center for Epidemiologic Studies-Depression scale (CES-D)

• State Trait Anxiety Inventory (STAI)

• Inventory of Depressive Symptomatology (IDS-SR)

• Beck Depression Inventory (BDI)

• General Health Questionnaire (GHQ)

New Prospective StudyGenes and Genotyping

Common disease – common variant

All patients share some genetic variants in a set of

genes. The combination determines disease

susceptibility. Variants have small effects.

Common disease-rare variant

All patients are unique have different (private)

mutations. Effect size can be large or small.

Types of Types of geneticgenetic variationvariation

ChromosomalChromosomal abnormalitiesabnormalities

translocationstranslocations, , deletionsdeletions, , inversionsinversions

CCopyopy NNumberumber VVariationariation

SmallSmall insertionsinsertions deletionsdeletions

indelsindels

SSingle ingle NNucleotideucleotide PPolymorphismsolymorphisms

large

small

SuggestionsSuggestions

More More emphasisemphasis onon CNVsCNVs and rare and rare variantsvariants

ChangeChange in in genotypinggenotyping platformsplatforms

MassiveMassive parallel sequencing parallel sequencing isis nownow possiblepossible

butbut

TechnologyTechnology cannotcannot solvesolve the the basicbasic problemproblem

DefinitionDefinition of the of the endophenotypeendophenotype is the most is the most important part of the important part of the studystudy

Documents

Team 1: Negative Psychological Attributes