Genetic Risk for Mental Illness

Genes

• small portion of DNA

• Regulate Biological traits

Genotype

genetic profile or makeup

• unique to you unless you have an IDENTICAL twin (not fraternal)

What % of the human genome varies between people

<1%

Phenotype

Observable characteristics of genetic variability

• tall vs short, blue eyes vs brown eyes

Genotype + Environment =

Phenotype

• Ex: Siamese cat markings cooling after birth (environment)

Monogenic

A trait, condition, or disease controlled or caused by a variant or mutation in a SINGLE gene

Polygenic

A trait or characteristic controlled by two or more genes working together

Mental illness IS

polygenic

• way less common to have monogenic traits than polygenic traits

Biomarker

measurable characteristic that indicate vulnerability or manifestation of a disorder (presence of the disorder)

• often unobservable to the unaided eye

• result from genetic variation

  • Ex: people with bipolar 1 have more colleen in their depressive episodes

Endophenotype

a special type of biomarker that is present EVEN WHEN THE DISORDER IS NOT PRESENT (probability of the disorder)

• is this person biologically vulnerable to develop a certain trait at some point (depression)

• cannot be seen with the unaided eye (phenotype)

• “Downstream” of genetic variations themselves (genotype)

  • schizophrenia can be identified by this

Genes —> Endophenotypes —> Biomarkers —> Phenotypes

have to work backwards unless the gene is monogenic

Heritability

Proportion of variance in a trait/condition (phenotype) explained by (not technically “caused by” or related to) genetic factors

Heritability population level estimate

• heritability estimates differences ACROSS PEOPLE

  • not the likely hood of someone being diagnosed with a disorder based on their family history

• Address why some people develop a trait and others do not

• Individual traits are the expression of BOTH genes and environment inseparable from one another

Most forms of psychopathology are…

highly heritable

Heritability is estimated with

variance and concordance

Variance

a measure of heterogeneity within a group (higher variance means greater unevenness)

• no variance = no heterogenity

• lots of variance = complicated heterogeneity

Concordance

the % of “matches” in a set of pairs (siblings, parent-child dyads)

• helps us establish heritability

• biological concordance is very important when looking for heritability

Heritable but NOT genetic traits

bathing, cleaning habits, hobbies, holidays, religion, cultural norms, language/accent, home ownership

Heritability estimates are UNSTABLE

• heritability varies over time

• heritability varies across environments

100% genetic DOES NOT MEAN

100% inevitable

Behavior genetics

• estimates heritability (ACE)

• how much of the variability in a trait is due to biological factos?

Molecular genetics

• identifies risk conferring genes

• How much of the variability in a trait is due to this specific gene variant?

Behavior genetic methods

family/pedigree studies, twin studies, adoption studies

Family/Pedigree Studies

Assume:

• family members more similar than non-family members

• Closer family more similar than more distant family

Confound: Environmental similarity

Adoption Studies

Test similarity of traits/disorders across children reared away from their families

Confound: restricted range of family environments

Confound: Environmental similarity

Twin Studies

Monozygotic (identical) vs Dizygotic (fraternal)

Estimate of heritability: H = 2(Mz - Dz)

Confound: Environmental similarity

Behavioral genetics - Limitations

• Overestimation of heritability (in part because of the EQUAL ENVIRONMENTS ASSUMPTION)

  • EEA: If there is a difference between people that is not environmental (height) is because of genes —> can lead to overestimation of heritability

• Unstable heritability effects over time

• the “gloomy prospect” of behavior genetics

  • substantial proportion of behavior influenced by nonshared environment

  • nonshared effects are random and compounded over time

Molecular Genetics - Methods

Linkage, Association—Candidate gene studies, Genome-Wide Association Studies (GWAS)

Linkage Study

• recruit families

• 2+ people w/ a rare disorder/trait

• Look for genetic markers

  • what variance do these people have in common?

• Monogenic traits

• difficult because we have a ton of genevariance

  • Only works for rare disorders and monogenic traits

Association

used in psychiatric genetics

Candidate gene studies

• identifying target gene (1 gene)

  • recruit people with that trait

• look for association with disorder

  • really inefficient because there are SO MANY genes that could attribute to a specific trait. Ex: schizophrenia

Genome-Wide Association Studies (GWAS)

• look for association with disorder

  • no loner need a candidate gene just people with the specific trait

• No target gene necessary

  • looking at correlation between the gene variance and having the trait

Molecular Genetics - Limitations

• Small portion of heritability accounted for (missing heritability)

  • end up only finding a gene variance that only accounts for a small fraction of variance

• Failure to replicate

  • the chance of being wrong rises for every additional gene that we try and fins a relationship with —> error rate of .05 multiplies over time