Strategies for investigating the genetics of psychiatric disorders Margit Burmeister, Ph.D. Molecular & Behavioral Neuroscience Institute (formerly Mental Health Research Institute) Department of Psychiatry Department of Human Genetics Neuroscience Program Bioinformatics Program University of Michigan, USA
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Strategies for investigating the genetics of psychiatric disorders Margit Burmeister, Ph.D. Molecular & Behavioral Neuroscience Institute (formerly Mental.
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Strategies for investigating the genetics of psychiatric disorders
Margit Burmeister, Ph.D.
Molecular & Behavioral Neuroscience Institute (formerly Mental Health Research Institute)
Department of Psychiatry
Department of Human Genetics
Neuroscience Program
Bioinformatics Program
University of Michigan, USA
Overview
•Heritability
•Terminology
•Linkage analysis
•Association studies – candidate genes
•Whole genome association studies
•Phenotypes
•Gene x environment interaction
Familiality is not heritability
•Bipolar Disorder, Depression, Schizophrenia and Alcoholism run in families
–But: Going to Medical School, being Catholic and speaking Mandarin also run in families.
•Heritable due to genes?
•Familial due to environment?
–Adoption: risk of child more influenced by biological parents (genetic) or adoptive (environment) parents?
–Twins: Monozygotic (MZ, identical) twins share 100% of genes, dizygotic (DZ, fraternal) twins share 50% of genes.
Twin concordance rates
(From: Plomin et al. 1994, Science 264: 1733-9)
Locus (plural: Loci)
The position on a chromosome of a gene or a genetic marker or a SNP
From Latin: Place
Alleleone of several forms of a locus
We inherit one allele from each parent
A locus that comes in several forms is called
polymorphic
Genetic marker
• DNA segment with known location on a chromosome whose inheritance can be followed
• DNA segments near each other on a chromosome tend to be inherited together
–so markers are an indirect way to track inheritance of an unknown gene
• Eye color and bristle length are used as easily recognizable genetic marker in Drosophila crosses
• Molecular markers are now used in human genetics
–Restriction fragment length polymorphisms (RFLPs).
–minisatellites, often also called VNTR markers
–microsatellite or STRP markers, e.g. CA/GT repeats
–SNPs: Single nucleotide polymorphism
Linkage analysis
Hypothetical marker with alleles A, B, C and D is is linked to the disease.In the first pedigree, allele A segregates with the disease, but in the second pedigree, allele B segregates with the disease. The indicated recombination event leads to allele C segregating with the disorder in the right branch.
What is linkage?
•Linkage is caused by loci (e.g. the risk gene and a genetic marker) being close to each other on a chromosome.
•The recombination fraction θ is the probability that, in any meiosis, there will be a recombination between them.
•θ=0.5 Mendelian segregation – no linkage
•θ=0.0 very tight linkage – no recombination.
How sure are we of linkage?
LOD score! Logarithm of Odds
(Probability of a particular family constellation
if the marker and disease locus are linked, with 10% recombination between them)
LOD (=0.1) = log ----------------------------------------------- (Probability of the same family constellation
of markers and disease if the marker is unlinked to the disease locus)
When is linkage significant?How many families are needed?
•LOD score of 3.0 - odds of 1000:1 are equivalent to p= 0.05
• With pedigree at hand, the best possible and a likely LOD score can be calculated.
• For a Mendelian disease, only 10 informative meioses are needed to get a LOD score of 3.03 – single families can be enough to find linkage
In this single family with a rare recessive disorder, we foundlinkage to 1p36 with a LOD score of 3.28
Unaffected; Affected; * DNA available
** ****
+*
** ** *
+
*
Family with recessive ataxia: SCASI
Complex Disorders
• Psychiatric disorders are complex - unlike Mendelian disorders, where a single mutation is both necessary and sufficient to bring about the disorder. Complexity can be due to
– genetic heterogeneity: many different risk genes
– small effect of each genetic factor: risk allele only increases risk by a small fraction
– diagnostic uncertainty: is a depressed or alcoholic subject in a Bipolar pedigree affected or not? What about a BP II subject?
– interaction with the environment
LOD score for complex traits – in multipoint analysis
(Probability of this particular data constellation
if a locus that increases risk for the disorder is in a particular chromosomal region)
LOD = log ----------------------------------------------- (Probability of this particular data constellation
• looks at chromosomal location, with the help of informative genetic markers
• powerful for simple Mendelian inheritance – no need for large samples
• assumes you know the genetic model
• no assumptions about the biology involved
• Assumes one or just a few genes are involved
• Families easily combined – add LOD scores
• More powerful if less heterogeneous subtypes can be defined (e.g. Bipolar Disorder with psychosis, antisocial alcoholism; early onset MDD)
• How do I follow up my positive linkage finding that showed 3 great POSITIONAL candidate genes in the region linked to the disease?
• How do I test whether a new BIOLOGICAL candidate gene is involved in alcoholism?
Association
Cases with Alcoholism Control sample
ALDH2*2 allele significantly protects against alcoholism in this sample from China (Chen et al., Am J Hum Genet. 1999,795-807).
ALDH2: 1/1: 304 (56%) 1/2: 218 (40%)
2/2: 23 ( 4%)
ALDH2: 1/1: 283 (83%) 1/2: 57 (17%)
2/2: 0
• Blood Flow to FaceBlood Flow to Face
• Blood Flow to BodyBlood Flow to Body
• Feel ItchyFeel Itchy
• Feel DizzyFeel Dizzy
• Feel TiredFeel Tired
• Feel AnxiousFeel Anxious
• Pounding HeadPounding Head
• Have SweatsHave Sweats
• Increased Heart RateIncreased Heart Rate
• Feel NauseousFeel Nauseous
These symptoms are experienced by those heterozygote forthe ALDH2*2 allele, and are severe in homozygotes
FLUSHING SYMPTOMS FLUSHING SYMPTOMS IN RESPONSE TO DRINKING ALCOHOLIN RESPONSE TO DRINKING ALCOHOL
Pharmacogenetic association
•Within a disease population, pharmacogenetic studies ask about drug side effects and/or response:
–drop outs versus drug continuation
–“responders” versus non-responders
Greer and Schatzberg, 2003
Am J Psychiatry 160:1830-5. Zanardi et al., 2001Biol. Psych. 50: 323-30.
Confounding of association by ethnicity (stratification)
Example: alcoholics in San Francisco. Asians (stripes) will be underrepresented among cases. ANY genetic marker more common among Asians will also be overrepresented in the controls – e.g. HLA.
cases controls
Linkage disequilibrium (LD)Linkage disequilibrium shows the history of the mutation.
starting chromosomes that exist in population at one point
A,a B,b C,c and D,d are different alleles at four different nearby loci:
A b c D
A b C d
a b C d
New mutation arises on one particular chromosome:
a B C d
Haplotype
Combination of specific SNPs on chromosome
A c D
A C d
a C d
I: A,c,D
II: A,C,d
III: a,C,d
We might find association of a disorder with haplotype III because of linkage disequilibrium with the (untyped) allele B!
a B C d
b
b
b
Applying the data:
• There are >10 Million SNPs in the human genome.
• Because of LD (linkage disequilibrium), typing 300,000-500,000 SNPs may give us some information about all the >10 Million SNPs
• Single SNPs as well as haplotypes can be tested for association with disease
High Neuroticism score is a risk factor for depression
• Endophenotypes or intermediate traits mark the genetic predisposition to a disorder, less dependent on the additional external triggers or vulnerabilities.
• Neuroticism is a psychological domain, measured with the established NEO-PI. Sample questions:
– I often feel tense and jittery (anxiety facet)
– Sometimes I feel completely worthless (depression)
–When I’m under a great deal of stress, sometimes I feel like I’m going to pieces (vulnerability)
• Twin and high risk studies suggest that a high Neuroticism score is a trait marker for depression
• At least in women, about 55% of the genetic liability to depression is shared with Neuroticism