Recurrence risks for schizophrenia in a Swedish National Cohort

Lichtenstein, Paul; Björk, Camilla; Hultman, Christina M.; Scolnick, Edward M.; Sklar, Pamela; Sullivan, Patrick F.

doi:10.1017/s0033291706008385

Cited by 170 publications

(147 citation statements)

References 22 publications

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“…Genetic epidemiology parameters of schizophrenia are classically quoted to be K¼1%, l 1 ¼8.6 and h L 2 ¼81%, 21 but results from a Swedish population sample of 49 million have revised these estimates to K¼0.4%, l 1 ¼9 and h L 2 ¼64%. 22,23 For K¼0.4% and l 1 ¼9, we predict h L 2 to be 63%, and for K¼1% and l 1 ¼8.6, we predict h L 2 to be 80%, reflecting that under a threshold liability model, the lower disease prevalence forces a lower estimate of h L 2 for the same l 1 . For K¼0.4% and h L 2 ¼63%, we predict the proportion of sporadic schizophrenia cases to be 90% (definition I) and 83% (definition II) in three-generation pedigrees with S¼2 ( Table 2).…”

Section: Discussionmentioning

confidence: 81%

Sporadic cases are the norm for complex disease

2009

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The results of genome-wide association studies have revealed that most human complex diseases (for example, cancer, diabetes and psychiatric disorders) are affected by a large number of variants, each of which explains a small increase in disease risk, suggesting a pattern of polygenic inheritance. At the same time, it has been argued that most complex diseases are genetically heterogeneous because many sporadic cases are observed, as well as cases with a family history. In this study, under the assumption of polygenic inheritance, we derive the expected proportion of sporadic cases using analytical methods and simulation. We show how the proportion of sporadic cases depends on disease prevalence (K) and heritability on the underlying liability scale (h L 2 ). We predict the underlying heritability and the proportion of sporadic cases for a range of human complex diseases, and show that this proportion is typically large. For a disease with h L 2 ¼63% and K¼0.4%, such as schizophrenia, 483% of proband cases are predicted to be sporadic (no affected first-, second-and third-degree relatives) in typical families (on an average, two children per couple). For the majority of these diseases, a large proportion of sporadic cases is expected under the polygenic model, implying that the observed large proportion of sporadic cases is not informative to the causal mechanism of a complex genetic disease. European Journal of Human Genetics (2010Genetics ( ) 18, 1039Genetics ( -1043 doi:10.1038/ejhg.2009 published online 14 October 2009 Keywords: sporadic case; polygenic inheritance; complex disease INTRODUCTION Large-scale, high-density genome-wide association studies (GWAS) have greatly facilitated the discovery of genetic variants that affect the predisposition to human complex diseases. 1 The results of recent GWAS suggest that the majority of susceptible loci have small contributions to phenotypic variation, which indicates that there should be a large number of susceptibility loci involved in the genetic basis of complex disease. [2][3][4][5][6][7][8] These findings are consistent with the polygenic model, proposed almost a century ago, 9 underlying the genetic etiology of complex diseases. At the same time, on the basis of the knowledge of family history, differentiation is often made between sporadic and familial cases. This differentiation implies some sort of genetic heterogeneity, either that environmental factors are more important in sporadic cases or that sporadic cases arise from new mutations of large effect size. Integrating this differentiation into an understanding of the genetic architecture of complex disease depends on the frequency of sporadic cases, consistent with the polygenic model.In this study, we investigate the relative proportion of sporadic and familial cases expected under the polygenic threshold model. We assume that disease susceptibility is genetically homogeneous in the population and the observed illness results from the accumulative effect of multiple common genetic and environment...

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Section: Discussionmentioning

confidence: 81%

Sporadic cases are the norm for complex disease

2009

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“…On the other hand, an important genetic overlap between SSD and BPD has been classically reported by both epidemiological (Gottesman 1991;Lichtenstein et al 2006) and molecular studies (Owen et al 2007). More recently, genome-wide approaches have evidenced a substantial shared polygenic contribution involving thousands of common genetic variants of small effect to the aetiology of these disorders (Lee et al 2013).…”

Section: Introductionmentioning

confidence: 94%

Involvement of NRN1 gene in schizophrenia-spectrum and bipolar disorders and its impact on age at onset and cognitive functioning

Fatjó‐Vilas

Prats

Pomarol‐Clotet

et al. 2015

The World Journal of Biological Psychiatry

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Objectives: Neuritin 1 gene (NRN1) is involved in neurodevelopment processes and synaptic plasticity and its expression is regulated by brain-derived neurotrophic factor (BDNF). We aimed to investigate the association of NRN1 with schizophrenia-spectrum disorders (SSD) and bipolar disorders (BPD), to explore its role in age at onset and cognitive functioning, and to test the epistasis between NRN1 and BDNF. Methods: The study was developed in a sample of 954 SSD/BPD patients and 668 healthy subjects. Genotyping analyses included 11 SNPs in NRN1 and one functional SNP in BDNF. Results: The frequency of the haplotype C-C (rs645649-rs582262) was significantly increased in patients compared to controls (P ¼ 0.0043), while the haplotype T-C-C-T-C-A (rs3763180-rs10484320-rs4960155-rs9379002-rs9405890-rs1475157) was more frequent in controls (P ¼ 3.1 Â 10 À5). The variability at NRN1 was nominally related to changes in age at onset and to differences in intelligence quotient, in SSD patients. Epistasis between NRN1 and BDNF was significantly associated with the risk for SSD/BPD (P ¼ 0.005). Conclusions: Results suggest that: (i) NRN1 variability is a shared risk factor for both SSD and BPD, (ii) NRN1 may have a selective impact on age at onset and intelligence in SSD, and (iii) the role of NRN1 seems to be not independent of BDNF. ARTICLE HISTORY

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“…We utilized data from a record linkage of six population-based registries in Sweden; personal identification numbers enabled accurate linkage (23) (buprenorfine+naltrexone) and N07BC02 (methadone)).…”

Section: Data Sourcesmentioning

confidence: 99%

“…By matching life time non-ADHD control subjects on birth year, sex and residential factors we ensured equal follow-up time. According to well-established procedures for nested casecontrol designs (23,28), controls were alive and living in Sweden and had not been diagnosed with ADHD at the time of the first ADHD diagnosis of the proband.…”

Section: Data Sourcesmentioning

confidence: 99%