Understanding Genetics of Schizophrenia Carlos N. Pato, M.D. , Ph.D. Professor and Chair of Psychiatry Center for Genomic Psychiatry Keck School of Medicine University of Southern California

Lifetime Risk for Schizophrenia 0.5-1.0% General Population 10-15% If a parent or sibling (including dizygotic twin) is schizophrenic 40% If both parents are schizophrenic 45-75% If monozygotic twin is schizophrenic (Same risk to children- Fisher) Risk = odds of developing illness. Both parents with the illness put you at higher risk than if single parent

Genes (DNA) do not read the DSM-IV. Go from epidemiologic point of view to genetics Phenotypes from DSM now IV may not match what we get in genetic factors. So as Cornblatt pointed out looking at certain features of an illness like psychosis can be important Genes (DNA) do not read the DSM-IV.

Phenotype Definition E F A H J D G C B Bipolar Disorder Schizophrenia Ven diagram highlighting the likely polygenetic and multifactorial nature of these syndromes and in fact thinking of them as syndromes rather than single illnesses- One can have PSYCHOSIS with either SCZ or BP B Psychosis

Genetic Strategies What is linkage ? What is an association ? What is a LOD score or a NPL ? What is an association ? How to understand statistical significance. Candidate genes Genome wide scans (genomic mapping) Gene expression arrays Gene expression arrays allow you to look at function not just structure Looking at homogenous samples seems to have been helpful

Schizophrenia on Chromosome 5q One of first linkage findings pointing the scz linkage on 5 q but with none above 3 which is what look for Linkage= a particular form of a chromosome in a region is being transmitted more commonly to patients that those without the illness. AND it implies that some genetic factor within that region is likely to play a causative role in the phenotype of the illness.

Region rich in candidate genes Glutamate receptor-GRIA1 GABA cluster-GABRA1, GABRA2 Serotonin Receptor-HTR4 Glycine Receptor-GLRA1 Glucocorticoid receptor-NR3C1 Adrenergic receptor-ADRB2 Neuregulin-NRG2 Kinase-CAMK2A These genes sit under this region so it seemed to make sense to look there, 5q region rich in interesting candidates , glutamate, gaba, 5ht YET TO DATE NO DEFINITIVE FINDINGS

Human Mapping Assay Accuracy >99% A rapid, reliable and cost-effective assay for simultaneously genotyping many thousands of SNPs distributed across the genome AA BB AB Generic complexity reduction scheme Hybridization-based allele discrimination Now we can map much more densely. The current standard is more than 1,000,000 snp (single nucleotide polymorphisms- meaning variation at a single base pair) This is a change from the original work that was to look at just 400 polymorphic markers (variations in sequence at larger sequences) gone away from these big pieces to be more specific which gives us much higher resolution Accuracy >99%

Transcript probes with the highest diagnostic utility for distinguising BP, SCZ, and control subjects Also focusing on expression profiling we have begun to develop possible diagnostic tests based on gene expression profiles from leucocytes (WBC). We have been able to discriminate with nearly 99% accuracy patients with Scz, from pts with BP, from controls. In these particular 5 genes had the highest diagnostic utility . What I mean is the pattern of expression of these 5 genes provided the most information of the dx *scz vs bp vs control that the subject fell into. Interesting there were 6 subjects in this 33 who were not able to be classified and in looking at there DSM diagnosis were schizoaffective!! The expression patterns of the 35 most predictive genes correctly classified all BP and control subjects and 27 of 33 SCZ subjects.

Genome-wide Survey of CNVs Nature (2008) 3380 patients with schizophrenia and 3139 ancestrally-matched controls identified three regions large (>500kb) deletions increase disease risk Deletions easier to detect because of their size and replicability compared to single point mutations (single SNP) CNV-copy number variants- less or more including deletions- chromo 22, 15, 1

Genome-wide Survey of CNVs Nature (2008) On chromosome 22q11.2 - identified deletions in ~0.3% of schizophrenia patients (P =0.00056 versus controls) Odds ratio = 21.6

Genome-wide Survey of CNVs Chromosome 22 deletion The red lines represent the areas of deletion in each of the 13 subjects. It differs a little from subject to subject put there is some overlap.

Genome-wide Survey of CNVs Nature (2008) On chromosome 15q13.2- identified deletions in ~0.3% of schizophrenia patients (P =0.00056 versus controls) Odds ratio= 17.9

Genome-wide Survey of CNVs Chromosome 15

Genome-wide Survey of CNVs Nature (2008) On chromosome 1q21.1 - identified deletions in ~0.3% of schizophrenia patients (P =0. 0.024 versus controls) Odds ratio= 6.6

Genome-wide Survey of CNVs Chromosome 1

Genome-wide Survey of CNVs Nature (2008) In the same issue of Nature, a parallel paper by DeCode showed the same results Extremely strong evidence for these relatively rare mutations Proves the necessity for extremely large studies DeCode is the Iceland group

MHC and Common Variants Nature, 2009 Common polygenic variation contributes to risk Rare variants likely to contribute to risk major histocompatibility complex strongly replicated association with schizophrenia DeCode is the Iceland group

Genomic Psychiatry Cohort We have established the goal of studying 30,000 patients and 30,000 controls Schizophrenia and Bipolar disorder We have begun to bring together the funding for this large-scale program The NIMH launched this program with an initial $25 million dollars in grants to USC and MGH/Broad

Future Directions Gene identification Gene expression Proteomics Treatment development At risk studies- with a focus on development of pre-clinical diagnosis + treatment We continue as we did from the beginning to id the genes involved and we are looking and their function as well as their structure. And in function we are going down to the proteins ( proteomics) that they code for.And we are starting to begin to think of studies of at risk and symptom treatment development and broader risk. If we could identify you as being at risk maybe we could tx you to prevent full blown illness