What Would Mendel Do?

Cüneyt Güzey M.D. Ph.D.

Function

Gene Protein

Genetics Biochemistry

Molecular Biology

Astraptes fulgerator

Mental Disorder A Complex Disease

Multiple Genes

Multiple Environments

Gene x Environment Interaction Gene x Gene Interaction or Epistasis

Adapted from Phillips et al. (2002) Genes Brain Behav 1:14.

Mode of inheritance

• Mental Diseases are inherited as complex diseases

• Mental disorders show no common Mendelian transmission

• It is likely that mental disorders are polygenic, with vulnerability arising from simultaneous impact of functional variations at several genes.

How investigate complex disorders?

Alleles, locus, genotype Alleles are different forms of a given variation in DNA sequence. Since each individual has two copies of each autosomal gene (derived from each parental chromosome) they also possess two alleles at any given locus, the combination of which makes up the genotype. Individuals in whom the two alleles are the same are homozygous, whereas those who possess two different alleles are heterozygous. The term wild-type may be used to point at the common variant in the population.

Definitions

Genome refers to the total genetic complement of an individual or species. Genotype refers to the set of genes an individual possesses that are relevant to the phenotype being considered. Phenotype refers to the observable characteristics (or symptoms of illness) under consideration.

Do they always agree?

It is known that individuals, although they carry a certain genetic variation, may not express the trait. Penetrance considers whether individuals express the trait or not. This may be of higher importance for the traits questioned in psychiatry, as the diagnosis in psychiatry based on cluster symptoms, and same symptoms may be shared by different diseases, while may not be shared by two patients with the same diagnosis.

Nature or nurture?

Most sound stand point is most likely observing all human characteristics as end products of the interplay between genes and environment. More important questions would therefore be: What are the relative contributions of genes and environment in particular situations? How can we use this knowledge to improve our current diagnosis and management of psychiatric illnesses?

Family history and mental illness

Most major mental illnesses have a strong genetic component. With each year that passes it will become increasingly important for us to be able to interpret the growing scientific literature on psychiatric genetics. If we take schizophrenia as an example, the largest and best-established risk factor is a positive family history. Relative risks of developing schizophrenia increase in line with genetic proximity to an affected individual (proband). The siblings of someone with schizophrenia are about eight times more likely than the general population to develop schizophrenia.

After a person has been diagnosed with schizophrenia in a family, the chance for a sibling to also be diagnosed with schizophrenia is 7 to 9 percent. If a parent has schizophrenia, the chance for a child to have the disorder is 10 to 15 percent. Risks increase with multiple affected family members.

Copyright © American Psychiatric Association.

All rights reserved.

From: Genetic Strategies in Psychiatric Disorders

FOCUS: The Journal of Lifelong Learning in Psychiatry 2010; 8:307-315

Lifetime Risk for Schizophrenia and Bipolar Disorder

Figure Legend:

Biemvenu et.al. 2011

Types of approaches

Classical genetic studies (family, twin and adoption studies) Linkage and association studies Association studies and Genome Wide Association Studies (GWAS) Chromosomal abnormalities.

Three questions

1. Does the disorder have an important genetic contribution? 2. In what region of the genome might a susceptibility gene be located? 3. Which gene in this region contributes to risk for the disorder and what abnormality or variation in the gene underlies susceptibility?

Family studies: Is the disorder

familial?

It makes intuitive sense that if a disorder is to some degree genetic, then the relatives of an affected individual will be more likely to be affected than someone with no such family history.

Does the disorder have an important genetic contribution?

Figure 3: Lifetime risk of schizophrenia – MZ versus DZ twins

Twin studies: Does genetic variation contribute towards susceptibility for the disorder? Clearly, if genes are indeed important risk factors, the disorder should co-occur more often in monozygotic (MZ) twins than in dizygotic (DZ) twins. Figure 3 shows that this is indeed the case for schizophrenia; the lifetime risk in an MZ twin of an affected individual is 55% compared to only 10% in a DZ twin.

Dizygotic Twins (DZ)

Different DNA Same environment • If same it must be due to

environment • If different it must be due to

genes

Monozygotic Twins (MZ) Same DNA Different environment • If same it must be due to

genes • If different it must be due to

environment

Heritability

68 % 2 %

30 %

Proportion of variability due to genes

Genes Family environment Environment

Common traits

Trait Heritability %

Corneal thickness 90

Freckles 90

Acne 90

Height 80

Osteoporosis 75

Diabetes 70

Obesity 70

Blood clotting 70

Back pain 65

IQ 65

Asthma-atopy 60

Trait Heritability %

Arthritis 60

Cataract 60

Heart disease 60

Neuvus count 55

Pain threshold 55

Migraine 50

Varicose veins 50

Menaouse 50

Blood pressure 45

Menarche 40

What is the influence of environment? Although twin studies are helpful, they tell us very little about the influence of environment (it is of interest that 45% of MZ twins of an affected proband do not develop schizophrenia, suggesting an important role for environmental factors in determining overall risk).

Genotype-environment interaction in schizophrenia-spectrum disorder. The British Journal of Psychiatry (2004) 184: 216-222 (

Genetic studies

• Study design

– Genomewide association studies (GWAS)

– Candidate gene association studies

Candidate genes

Candidate genes are genes that are suspected of contributing to a disease by virtue of their location or function. Once regions that are likely to contain genes of interest have been identified, association studies can test whether a given candidate gene within these regions is implicated

Genomewide Assocition Studies

Several GWAS studies have been completed on: autism Alzheimers disease bipolar disorder schizophrenia.

Several others are in progress for: anorexia nervosa ADHD major depression drug and alcohol use disorders obsessive-compulsive disorder.

Association studies

Importantly, many of the genetic variants identified from these studies are for genes not previously known to be associated with the disorder, for example: the CLU and PICALM genes in Alzheimer’s disease ZNF804A in schizophrenia ANK3 and CACNA1AC in bipolar disorder. These novel findings open up a range of new avenues of potential research into the classification and pathophysiology of psychiatric disorders.

Risk genes for schizophrenia (at last ?)

A large number of linkage studies have led to the identification of three genes that are strongly implicated in the pathogenesis of schizophrenia. These genes have been named: dysbindin (DTNBP1, located on chromosome 6) neuregulin (NRG1, on chromosome 8) D-amino acid oxidase activator (DAOA, on chromosome 13).

Chromosomal analysis

The DISC1 story

The genogram shows five generations of an extended family from Scotland.

This family are highly unusual in that several members have what is called a ‘balanced translocation’ between chromosomes 1 and 11. A chunk of the tip of chromosome 1 has swapped over with a chunk of chromosome II and has been inherited down through the family tree.

The DISC1 story

This picture shows a metaphase spread from a member of the family who carries the translocation. Chromosome 1 material is visualised in red, and chromosome 11 in green. It can be seen that a small piece of chromosome 11 has been moved onto the end of chromosome 1 (labelled ‘der1’) and an even smaller piece of chromosome 1 has been moved onto chromosome 11 (labelled ‘der11’).

The DISC1 story

Diagnostic assessment of this family over many years has revealed that most of those carrying this chromosomal translocation also suffer from major psychiatric disorders such as schizophrenia and bipolar disorder. This has led to a systematic search of the chromosomal breakpoint region for vulnerability genes, on the basis that one or more of these disrupted genes might cause schizophrenia and/or bipolar disorder in this family.

Subsequent work has demonstrated that the DISC1 protein is involved in cellular functions such as cell migration and neuronal outgrowth that are consistent with a neurodevelopmental model of psychotic illnesses.

What happens next?

Once the 'breakpoint region' of a chromosome has been located, the next question is: Which gene in this breakpoint region contributes to risk for a disorder and what abnormality or variation in the gene underlies susceptibility? Once linkage and/or association analysis maps disease susceptibility to a particular region, the search begins for the causative variant that might be involved in the pathogenesis of the disorder. In this respect, the publication of the Human Genome Project in 2003 has been a tremendous step forward. This project determined the sequence of the 3 billion base pairs in human DNA and identified each of the 25,000 genes in the genome.

The HapMap is a similar international project to the Human Genome Project. This project is currently identifying a haplotype map of the human genome which will describe the common patterns of human DNA sequence variation. This project has led to considerable advances in the detection of risk genes for complex disorders such as schizophrenia and bipolar disorder.

Recent technical advances

1.Aa detailed knowledge of the anatomy of the genome in terms of its sequence and gene content and the sequence variation all common DNA. 2. Develeopment of cheap microarray based genotyping platforms 3. accumulation of large sample sizes

Implications for future research

These three developments now mean that the most powerful study design for small genetic effects, association, can now be applied across the genome rather than restricted to candidate genes selected on the basis of a functional hypothesis. Consequently, it is hoped that hitherto unsuspected genes and pathophysiological pathways will be identified, thereby opening the door to new avenues of research in psychiatry.

New treatments based on understanding pathogenesis

With the identification of susceptibility genes, there is far greater potential to develop treatments that can be targeted effectively for the individual. It can be expected that findings in molecular genetics will lead on to novel treatments that are better targeted at disease mechanisms and have fewer adverse effects. Indeed, this is the primary motivation for the study of psychiatric genetics. It is, however, important to recognize that even if we know which genes make people susceptible to a disorder, it may be many years before we will realize the goal of effective, novel treatments.

How can genetics improve our classification of mental illness?

Distinction among psychiatric disorders, such as bipolar disorder and schizophrenia in diagnostic routines is undoubtedly useful. Recent genetic and epidemiological findings suggest that there is a considerable degree of aetiological overlap between these disorders (Craddock and Owen, 2005). A recent Swedish study of two million nuclear families found increased risks of both schizophrenia and bipolar disorder for the first-degree relatives of probands with either disorder (Lichtenstein et al, 2009). It can be expected that in the future molecular genetic epidemiology will inform a classification of major mental illness that is based on aetiololgy rather than on patterns of symptoms.

WHERE ARE WE HEADING?

“We do not stand alone” 1936

“60000 RM this is what this person suffering from hereditary defects costs the Community of Germans during his lifetime Fellow Citizen, that is your money, too” 1938

Only Germany? Think again!

States proud to conduct sterilization of “genetically ill” people. Target populations were the “mentally ill”.

Summary Perhaps more than any other field of psychiatric research, molecular genetics has the potential to significantly impact on the way that we diagnose, classify and treat all of the major mental illnesses. Over the next generation, genetic epidemiology will inform changes to the diagnosis and treatment of serious mental disorders. Molecular genetic investigations of psychiatric disorders are already identifying key proteins involved in the pathogenesis of mental illnesses.

Summary

The nature-nuture debate is over: understanding gene-environment interplay is the next step forward. Genetic studies have produced strong evidence for genes involved in schizophrenia, bipolar disorder and Alzheimer’s disease. For the major psychiatric disorders we can expect that a large number of relatively common gene variants of small effect will influence pathogenesis. Molecular genetics will produce new avenues for the development of novel treatments. Pharmacogenomics holds promise for tailoring treatments to individuals. Genetic research in psychiatry, as part of the overall drive to understand what causes mental illnesses, will ultimately reduce stigma.