Genetics and Conceptual Framework

Question 1

What is the contribution of genetic factors?

Answer 1

Get information about this from family studies (not conclusive, as family members share not only genes but also environments), adoptive studies, and twin studies

Question 2

What are adoption studies?

Answer 2

Compare the rates of a disorder in biological relatives to those in adoptive relatives. Affected by a number of biases (e.g. reasons for adoption, non-random matching in placement) and limitations (e.g. small sample size, uncontrolled for prenatal environment)

Question 3

What are the different types of adoption studies?

Answer 3

Adoptee studies (adoptees of an affected parent vs. adoptees of healthy parents). Adoptee’s family studies (biological vs. adoptive relatives of affected adoptees). Cross-fostering studies (adoptees with affected biological parents and healthy adopted parents vs. adoptees with healthy biological parents and affected adopted parents)

Question 4

What are twin studies?

Answer 4

Compare the rates of concordance (i.e. both twins with the same disorder) in MZ twins to DZ twins. Difference in concordance between MZ and DZ twins indicates the size of heritability and the presence of ‘shared’ vs. ‘non-shared’ environmental factors.

Question 5

Are twin studies important?

Answer 5

Twin studies are the most important tool to estimate the genetic contribution to a phenotype (e.g. schizophrenia, depression, autism). Heritability - the proportion of the liability to a phenotype that is accounted for by additive genetic effects.

Question 6

What are types of genetic variation?

Answer 6

There are three main types of genetic variants relevant to the aetiology of mental disorders: chromosomal abnormalities, polymorphisms and mutations, and copy number variation.

Question 7

What are chromosomal (cytogenetic) abnormalities (type of genetic variation)

Answer 7

The abnormality can be in a number of chromosomes, a deletion or duplication of part of a chromosome, or translocation of part of a chromosome to another. Chromosomal abnormalities are responsible for genetic syndromes associated to Intellectual Developmental Disorders, e.g. down syndrome (trisomy 21), turner syndrome (XO), Klinefelter syndrome (XXY), fragile x syndrome (part of the x chromosome is missing), and Velocardiofacial syndrome (part of one copy of chromosome 22 is deleted)

Question 8

What are polymorphisms and mutations (type of genetic variation)

Answer 8

No two people share exactly the same genome (except MZ twins). DNA sequence variants are called polymorphisms or allelic variants. The two alleles of every autosomal gene may be identical (homozygosity) or differ (heterozygosity). Most polymorphisms involve change in a single nucleotide. Most do not lead to changes in protein encoding and have no known consequences. Some may be beneficial or harmful in a probabilistic sense. There are very rare polymorphisms (<1%) that are by definition harmful and are called mutations

Question 9

What are copy number variation (type of genetic variation)

Answer 9

Between the extremes of chromosomal abnormalities and SNP, an intermediate type of genetic variation has been identified recently: structural variation or Copy Number Variation (CNV). They are duplications or deletions of stretches of DNA ranging in size from hundreds to thousands of nucleotides and they may be thought of as miniature chromosomal abnormalities. Large CNV’s and those that disrupt key genes are more likely to be harmful. CNV’s can either be inherited or are not seen in either parent

Question 10

What is the Mendelian model of inheritance?

Answer 10

Dominant, recessive, or X-linked mutations. Very rare (e.g. familial Alzheimer’s disease and Huntington’s disease). Best studied using genetic linkage

Question 11

What are Non-Mendelian models of inheritance?

Answer 11

Complex genetic disorders. No gene is either necessary or sufficient to cause the disorder. The ‘genetic architecture’ (i.e. the number of genes and genetic variants involved, and how they operate to increase risk) of most mental disorder is still unclear. Much of the heritability come from genetic variants that are common in the population (polymorphism) but are important epidemiologically. Each of the common genetic variants confers only a small (additive) increase in risk to the individual: common disease-common variant (CD-CV) model. Best studied using genetic association

Question 12

What are genetic association studies?

Answer 12

Genetic association studies compare the frequency of genetic polymorphism in a group of individuals who have the disorder to that of control individuals. Easy to perform using DNA samples from blood or cheek swabs and to genotype using methods based on polymerase chain reaction (PCR). Have candidate gene studies and Genome-Wide Association Studies (GWAS)

Question 13

What are candidate gene studies?

Answer 13

Phenotypes identified based on animal or clinical data (e.g. dopamine receptors for schizophrenia) suggest plausible candidate genes. Many candidate gene association studies have been conducted in psychiatry. Some findings have proven robust but most not, reflecting two major limitations

Question 14

What are the two major limitations of candidate gene studies?

Answer 14

1 - There are about 20000 genes in the human genome and hundreds of thousand of SNPs. The prior probability that a gene (let alone an SNP) is associated to a given genotype is very low. Hence, the high probability of false-positive (which are more likely to be published than negative results)
2 - differences in ethnic background between ‘cases’ and controls may lead to artefacts because the frequency of polymorphism can very markedly depending of ethnic stratification. e.g. the frequency of COMT-Met158 allele varies from 1% to 60% depending on the population

Question 15

Why is finding genes for psychiatric disorders difficult?

Answer 15

Starting with ‘wrong’ clinical phenotypes. Genes are highly unlikely to map on to current diagnostic categories, yet samples are used collected based on the latter. Stronger genotype-phenotype relationships may be seen if categories are broadened (e.g. psychosis rather than schizophrenia or bipolar disordeR), or decomposed (e.g. schizophrenia into cognitive deficits and psychotic symptoms).
No ‘major genes’ exist. Each gene on its own contributes only a small fraction of the heritable risk. Different genes may affect risk in different people (genetic heterogeneity). Within a gene, different variants may affect risk in different people (allelic heterogeneity). The presence of phenocopies and de novo mutations. Gene-gene interactions (epistasis). Gene-Environment interactions. Epigenetics

Question 16

What are Genome-Wide Association Studies (GWAS)?

Answer 16

GWAS have largely supplanted candidate gene studies. They do not require any prior hypothesis (or bias) about the aetiology of a disorder. Hundreds of thousands of SNPs, selected to cover the whole of the genome, can be tested at the same time. A person’s DNA is added to a silicon ‘chip’ containing probes for the SNPs. A scanner reads the genotypes of each SNP. GWAS have led to the discovery of the existence and importance of CNVs. Because so many SNPs tested, significance criterion needs to be lowered, which requires large samples

Question 17

What are problems with DSM and ICD?

Answer 17

Based on consensus, don’t align with findings from neuroscience and genetics. Boundaries of categories have not been predictive of treatment response or led to development of new treatments. Signs and symptoms don’t capture fundamental underlying mechanisms of dysfunction

Question 18

What is RDoC (‘beyond’ DSM and ICD)

Answer 18

In 2010, the NIMH launched the RDoC initiative in “an attempt to create a new kind of taxonomy for mental disorders by bringing the power of modern research approaches in genetics, neuroscience, and behavioural science to the problem of mental illness”

Question 19

What 3 key points is the RDoC initiative based on?

Answer 19

First: mental illness = disorders of brain circuits.
Second: dysfunction in brain circuits can be identified with the tools of clinical neuroscience.
Third: data from genetics and clinical neuroscience leads to biosignitures that will facilitate clinical management.
This is still a vision for the future, given the still rudimentary nature of data relating measures of brain function to clinically relevant individual differences in genomics, pathophysiology, and behaviour

Question 20

What is the RDoC matrix?

Answer 20

The RDoc matrix is constructed around 5 major domains of human functioning. These domains reflect major systems of emotion, cognition, motivation, and social behaviour. Within each domain are behavioural elements, processes, mechanisms, and responses, called constructs. Constructs comprise different aspects of the overall range of functioning from normal to abnormal, with the understanding that each is situated in, and affected by, environmental and neurodevelopment contexts. Measurement of constructs can occur using several different methods termed units of analysis. These include genetic, molecular, neurocircuit, and behavioural assessments.