Lecture 4 - Heritability of Affective Disorders Flashcards
What is the heritability of MDD (from twin studies)?
Roughly 30-40%
If a parent or sibling has MDD - risk increases by 2-3x
Why are candidate gene studies no longer used to study the genetics of psychiatric disorders?
Restricted quality control
Difficult to replicate and findings have not been replicated
Vaguer statistical testing
Low reliability (can’t control for error and can’t control DNA samples)
Why are genome wide association studies now used?
Better quality control Unbiased approach Replicated findings Clear statistical methods - rigour Can control for artefacts (e.g. multiple comparison)
Outline the types of genetic variation that can be investigated for?
Single nucleotide polymorphisms - one allele base change
Variable tandem repeats - blocks of bases repeated
Copy number variations - blocks of >1kb are repeated or deleted
Insertions/Deletions
Inversions
What are genome wider association studies?
Studies of genetic variation across a population to examine the genetic basis of a disease
Work by finding paired associations between genotypes at each locus in individuals with the disease compared to those without
What is linkage disequilibrium and how has it been useful for GWAS?
LD refers to a non-random association of two alleles at different loci (locations on a gene)
As a single SNP will be in linkage disequilibrium with another SNP it will allow the identification of another genetic variation that could account influence the disease
What is the significance of GWAS and why is it set to this?
p - 5 x 10-8
Set to this as many tests are being conducted - increases likelihood of false positive.
This is also affected given the test of an a SNP to disease status is only partly independent as this SNP may have strong LD with another.
What is imputation in GWAS?
Allows the completion of missing genotypes at particular locations via the use of genomic refence panels
Increases the richness of the data and is cheaper than whole genome sequencing
State some limitations of GWAS
Hard to identify true underlying gene and the biological method - GWAS only shows the locus
GWAS do not detect all genetic variation - rare variants, copy number variation, de novo variants and complex genetic regions (MHC) may not be captured
GWAS mainly captures common variation with low effect sizes
What was the CONVERGE study?
Low depth whole-genome sequencing study amongst severe depressed Chinese women.
Found two regions with genome-wide significance on chromosome 10 - near SIRT1 and LHPP
Mixed results with regards to replication of these findings
Name a specific gene with several SNPs identified from the PGC meta-analysis using 23andMe data?
Neuronal Growth Regulator 1
BMI was also associated to this gene
MD cases had several SNPs in LD
Why do MDD GWAS need larger samples than Schz
Increased heterogeneity
MDD GWAS require at least 4-5x sample sizes than Schz studies
How did Howard et al identify 102 SNPs associated with depression?
More broadly defined cases - “have you ever needed treatment for anxiety, depression or tension?”
- Some genetic variation identified here also overlapped with smoking and neuroticism
- MR found depression risk factor explained smoking outcome
- MR found neuroticism outcome explained depression outcome
How did the UK biobank use trauma and mental health assessment questionnaires to assess for shared genetic basis between trauma and MDD?
Existing questionnaires for depression (PHQ-9), anxiety (GAD-7), mania and alcohol consumption.
Over two years added extra questions on childhood, adult and catastrophic trauma.
These items were correlated to measures of MDD
Two or more of selected items (those with OR > 2) from these categories were used to create a trauma exposed group of cases (MDD with trauma)
and controls (MDD with (without?) trauma)
Compared genetic variation between MDD and Trauma. Significant correlation (0.62) in full cohort.
The heritability of MDD increases with exposure to trauma
Depression PRS and trauma interact in a multiplicative (x) way
What is the GLAD project?
Genetic links to anxiety and depressive disorders
Part of the UK NIKR mental health BioResource
To explore genetic predictors of depression and anxiety disorders
To explore environmental risk factors and co-morbidities
To facilitate a re-contactable resource
Develop a database of contact details
