Schizophrenia Whitepaper

Schizophrenia Whitepaper
Orchid's team of genetic experts has released a genetic risk score (GRS) for schizophrenia.
Written by  Orchid Team
Orchid has released advanced genetic risk scores (GRS) for a variety of diseases. Here we present our data on our GRS of schizophrenia.

Schizophrenia

Schizophrenia is a severe and often debilitating long-term psychiatric condition, characterized by persistent cognitive deficits, frequent hallucinations and/or delusions, and social withdrawal [1]. The exact cause of the disease is unknown [2] but a study conducted on 31,524 twin pairs  estimated the disease to be about 65.1 to 88.2% heritable [3].  The disorder exhibits a polygenic architecture, meaning it is influenced by many genes, each contributing a small effect. A Genome-Wide Association Study (GWAS) is a research approach used to identify genetic variations associated with specific diseases. GWAS scans the genomes of many individuals to find genetic markers, often single nucleotide polymorphisms (SNPs), that occur more frequently in people with a particular disease compared to those without the disease. Researchers have analyzed genomes of 150,064 individuals of European ancestry including 36,989 cases (individuals with schizophrenia) and 113,075 healthy controls [4].

Genetic risk score (GRS) 

A genetic risk score (GRS) is a method to quantify the genetic component of an individual's risk for a specific disease that incorporates the cumulative effect of multiple genetic variants. The GRS for schizophrenia includes over 900,000 variants.

Clinical Impact and Prevalence 

About 1.5 million Americans (or 0.45% of the population) currently live with schizophrenia, and the disease is typically diagnosed in the early-mid 20s for males, and the early-mid 30s for females [5], [6]. The NIH has established three categories of symptoms for schizophrenia: psychotic symptoms, including delusions and hallucinations, negative symptoms, including reduced motivation and anhedonia, and cognitive symptoms, including problems with focusing or retaining information [5]. People with schizophrenia have an average lifespan that is 10 years shorter, mostly through higher suicide rates [7]. Like many psychiatric disorders, schizophrenia is very expensive for health systems and in 2001, was the 8th leading cause of DALY’s (a measure of disability that quantifies the years of healthy life lost) for young adults (15-44 years) [8]. Treatment of schizophrenia is through antipsychotic drugs, ideally with substantial social support [1], though patients tend to have residual symptoms and deficits [9].

Performant schizophrenia risk stratification   

Validated using a large cohort of individuals with known disease status 

Within the UK Biobank cohort, adults in the 99th percentile of genetic risk have a 1.44% absolute risk of schizophrenia, compared to 0.34% for the baseline rate. Baseline rate is the prevalence of the disease in the entire reference population. 

 

Figure 1: Risk gradient for schizophrenia. Each blue dot represents a percentile of Genetic Risk Score, with its percent prevalence in UK Biobank self-reported White British in the y-axis. The black line represents the predicted prevalence from a logistic regression derived from the data.

In the UK Biobank, cases were identified using self-reported schizophrenia (UK Biobank field 20002, code 1289) relevant ICD-9 and -10 diagnosis codes. See our supplementary table for full details. In the validation, prevalence of the disease increased with GRS. Using our phenotype definition, in our sample of self-reported white British, there were 1,386 cases of schizophrenia and 407,144 controls (prevalence of 0.34%).

Table 2: Prevalence and odds ratios of schizophrenia in elevated genetic risk subgroups.

Identification of adults at 4-5 times the baseline risk of schizophrenia  

Adults in the 99th percentile of genetic risk develop schizophrenia at 4.24 times the baseline rate, with an odds ratio of 4.34.

Additional notes

There is genetic overlap between schizophrenia and other psychiatric disorders, such as bipolar disorder and autism spectrum disorder, suggesting shared genetic risks. In addition to common SNPs, rare genetic variants like copy number variants (CNVs) also contribute to schizophrenia risk. Studies by Stefansson et al. and others have found that certain CNVs are more frequent in individuals with schizophrenia [10]. Most genome wide association studies (GWAS) have been conducted in European populations, but recent studies are expanding to include diverse ethnic groups, and additional statistical techniques are being developed to improve the portability and performance of genetic risk scores [11].

Citations

1. NHS. Overview - Schizophrenia. [cited 5 Jan 2022]. Available: https://www.nhs.uk/mental-health/conditions/schizophrenia/overview/

2. NHS. Causes - Schizophrenia. [cited 5 Jan 2022]. Available: https://www.nhs.uk/mental-health/conditions/schizophrenia/causes/

3. Hilker R, Helenius D, Fagerlund B, Skytthe A, Christensen K, Werge TM, et al. Heritability of Schizophrenia and Schizophrenia Spectrum Based on the Nationwide Danish Twin Register. Biol Psychiatry. 2018;83: 492–498.

4. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511: 421–427.

5. National Institute of Mental Health. Schizophrenia. [cited 5 Jan 2022]. Available: https://www.nimh.nih.gov/health/topics/schizophrenia

6. NAMI: National Alliance on Mental Illness. Mental Health By the Numbers. [cited 5 Jan 2022]. Available: https://www.nami.org/mhstats

7. Mortensen PB, Juel K. Mortality and causes of death in first admitted schizophrenic patients. Br J Psychiatry. 1993;163: 183–189.

8. Rössler W, Salize HJ, van Os J, Riecher-Rössler A. Size of burden of schizophrenia and psychotic disorders. Eur Neuropsychopharmacol. 2005;15: 399–409.

9. Sarkar S, Hillner K, Velligan DI. Conceptualization and treatment of negative symptoms in schizophrenia. World J Psychiatry. 2015;5: 352–361.

10. Stefansson, H., et al. (2008). Large recurrent microdeletions associated with schizophrenia. Nature, 455(7210), 232-236.

11. Zhang Q, Privé F, Vilhjálmsson B, Speed D. Improved genetic prediction of complex traits from individual-level data or summary statistics. Nat Commun. 2021;12: 4192.

Orchid Health supports open research data initiatives while abiding by the terms of use on all sourced genetic risk models and datasets.  Orchid does not train mental health models from restricted raw datasets including but not limited to that of the Psychiatric Genomics Consortium.

Appendix: Disease case identification and number of cases in UK Biobank

*Type 1 diabetes was defined as a combination the following inclusion and exclusion criteria:

  • Self-diagnosed diabetes (any type)
  • No self-diagnosed Type 2 diabetes
  • Age of diabetes onset between 0 and 20 years
  • Started insulin within one year of diagnosis of diabetes
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