A Population-Based Study of Shared Genetic Variation Between Premorbid IQ and Psychosis Among Male Twin Pairs and Sibling Pairs From Sweden

Fowler, Tom; Zammit, Stanley; Rasmussen, Finn

doi:10.1001/archgenpsychiatry.2011.1370

Cited by 52 publications

(23 citation statements)

References 36 publications

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“…The findings are in agreement with the small (7 %) genetic variance for psychosis shared with pre-morbid IQ (Fowler et al 2012). Thus, although there is a robust association between schizophrenia and intelligence, this may not be due mainly to shared genetic factors.…”

Section: Discussionsupporting

confidence: 87%

“…First, IQ measurements in patients could be influenced by the presence of psychotic symptoms, or the use of medication or illicit drugs, which could have partly masked the genetic effects. Second, total IQ was estimated by four out of 11 WAIS subtests, which is less precise than an estimate based on all 11 subtests, although the shortened version is more widely used (Fowler et al 2012). Furthermore, the lack of effect of global CNV measures on IQ does not exclude an effect of individual CNVs at specific chromosomal locations on schizophrenia susceptibility and IQ.…”

Section: Discussionmentioning

confidence: 99%

“…It has been associated with lower pre-morbid general intelligence (IQ) (Khandaker et al 2011; Fowler et al 2012), with cognitive decline prior to illness onset (Reichenberg et al 2010) and with cognitive decline during the course of the illness (Hedman et al 2012), although the latter is controversial. Both schizophrenia and IQ are largely determined by genetic factors, with estimated heritabilities of 80 % (Cardno et al 1999) and 70 % (Fowler et al 2012) respectively. Several studies have identified genetic variants that affect these respective phenotypes.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, novel candidate genes can be identified based on the overlap in high-ranking SNPs associated with schizophrenia and its endophenotypes. IQ is another candidate endophenotype for this approach because of its strong association with disease (Mesholam-Gately et al 2009), high heritability (Fowler et al 2012), normally distributed quantitative measures and relatively straightforward assessment.…”

Section: Introductionmentioning

confidence: 99%

“…However, a large Swedish population cohort study of twins and sib pairs ( n =374 199 subjects) found that the broader phenotype of psychosis explained a much smaller amount (1 %) of variation in pre-morbid intelligence at age 18, although this phenotypic correlation was also largely determined by shared genetic influences (for 91 %). However, because the correlation was small, the genetic variance for pre-morbid IQ shared with psychosis was only 7 % (Fowler et al 2012). This suggests that, of all genetic variants associated with pre-morbid IQ, few will influence psychosis, and vice versa .…”

Section: Introductionmentioning

confidence: 99%

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Schizophrenia genetic variants are not associated with intelligence

Scheltinga¹,

Bakker²,

Haren³

et al. 2013

Psychol. Med.

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Background Schizophrenia is associated with lower pre-morbid intelligence (IQ) in addition to (pre-morbid) cognitive decline. Both schizophrenia and IQ are highly heritable traits. Therefore, we hypothesized that genetic variants associated with schizophrenia, including copy number variants (CNVs) and a polygenic schizophrenia (risk) score (PSS), may influence intelligence. Method IQ was estimated with the Wechsler Adult Intelligence Scale (WAIS). CNVs were determined from single nucleotide polymorphism (SNP) data using the QuantiSNP and PennCNV algorithms. For the PSS, odds ratios for genome-wide SNP data were calculated in a sample collected by the Psychiatric Genome-Wide Association Study (GWAS) Consortium (8690 schizophrenia patients and 11 831 controls). These were used to calculate individual PSSs in our independent sample of 350 schizophrenia patients and 322 healthy controls. Results Although significantly more genes were disrupted by deletions in schizophrenia patients compared to controls (p=0.009), there was no effect of CNV measures on IQ. The PSS was associated with disease status (R2=0.055, p=2.1×10−7) and with IQ in the entire sample (R2=0.018, p=0.0008) but the effect on IQ disappeared after correction for disease status. Conclusions Our data suggest that rare and common schizophrenia-associated variants do not explain the variation in IQ in healthy subjects or in schizophrenia patients. Thus, reductions in IQ in schizophrenia patients may be secondary to other processes related to schizophrenia risk.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Schizophrenia genetic variants are not associated with intelligence

Scheltinga¹,

Bakker²,

Haren³

et al. 2013

Psychol. Med.

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Differential Effects of Common Variants inSCN2Aon General Cognitive Ability, Brain Physiology, and messenger RNA Expression in Schizophrenia Cases and Control Individuals

et al. 2014

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One approach to understanding the genetic complexity of schizophrenia is to study associated behavioral and biological phenotypes that may be more directly linked to genetic variation.OBJECTIVE To identify single-nucleotide polymorphisms associated with general cognitive ability (g) in people with schizophrenia and control individuals. DESIGN, SETTING, AND PARTICIPANTS Genomewide association study, followed by analyses in unaffected siblings and independent schizophrenia samples, functional magnetic resonance imaging studies of brain physiology in vivo, and RNA sequencing in postmortem brain samples. The discovery cohort and unaffected siblings were participants in the National Institute of Mental Health Clinical Brain Disorders Branch schizophrenia genetics studies. Additional schizophrenia cohorts were from psychiatric treatment settings in the United States, Japan, and Germany. The discovery cohort comprised 339 with schizophrenia and 363 community control participants. Follow-up analyses studied 147 unaffected siblings of the schizophrenia cases and independent schizophrenia samples including a total of an additional 668 participants. Imaging analyses included 87 schizophrenia cases and 397 control individuals. Brain tissue samples were available for 64 cases and 61 control individuals. MAIN OUTCOMES AND MEASURESWe studied genomewide association with g, by group, in the discovery cohort. We used selected genotypes to test specific associations in unaffected siblings and independent schizophrenia samples. Imaging analyses focused on activation in the prefrontal cortex during working memory. Brain tissue studies yielded messenger RNA expression levels for RefSeq transcripts. RESULTSThe schizophrenia discovery cohort showed genomewide-significant association of g with polymorphisms in sodium channel gene SCN2A, accounting for 10.4% of g variance (rs10174400, P = 9.27 × 10 −10 ). Control individuals showed a trend for g/genotype association with reversed allelic directionality. The genotype-by-group interaction was also genomewide significant (P = 1.75 × 10 −9 ). Siblings showed a genotype association with g parallel to the schizophrenia group and the same interaction pattern. Parallel, but weaker, associations with cognition were found in independent schizophrenia samples. Imaging analyses showed a similar pattern of genotype associations by group and genotype-by-group interaction. Sequencing of RNA in brain revealed reduced expression in 2 of 3 SCN2A alternative transcripts in the patient group, with genotype-by-group interaction, that again paralleled the cognition effects. CONCLUSIONS AND RELEVANCEThe findings implicate SCN2A and sodium channel biology in cognitive impairment in schizophrenia cases and unaffected relatives and may facilitate development of cognition-enhancing treatments.

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Risks for Nonaffective Psychotic Disorder and Bipolar Disorder in Young People With Autism Spectrum Disorder

et al. 2015

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IMPORTANCE Whether individuals with autism spectrum disorder (ASD) are at increased risk for nonaffective psychotic disorder (NAPD) or bipolar disorder (BD) is unknown. OBJECTIVE To test whether the risks for NAPD and BD in individuals with ASD are increased and whether these risks are higher than those of their siblings not diagnosed as having ASD. DESIGN, SETTING, AND PARTICIPANTS We performed a nested case-control study of all individuals 17 years or younger who ever resided in Stockholm County, Sweden, from January 1, 2001, through December 31, 2011 (Stockholm Youth Cohort). We included cohort members ever diagnosed as having ASD (n = 9062) and their full siblings never diagnosed as having ASD. Each case was matched with 10 control individuals of the same sex born during the same month and year. Using Swedish registers, cases, siblings, and controls were followed up until December 31, 2011. By then, the oldest individuals had reached the age of 27 years. EXPOSURES Autism spectrum disorder, registered before age 16 or 28 years. We distinguished between ASD with and without intellectual disability (ID). MAIN OUTCOMES AND MEASURES We calculated odds ratios (ORs) for NAPD and BD adjusted for age, sex, population density of place of birth, personal or parental history of migration, hearing impairment, parental age, parental income, parental educational level, and parental history of psychiatric disorder. RESULTS The adjusted ORs for NAPD and BD for cases with non-ID ASD registered before age 16 years were 5.6 (95% CI, 3.3-8.5) and 5.8 (95% CI, 3.9-8.7), respectively; the adjusted ORs for cases with ID ASD were 3.5 (95% CI, 2.0-6.0) and 1.8 (95% CI, 0.8-4.1). The adjusted ORs for NAPD and BD in cases with non-ID ASD registered before age 28 years were 12.3 (95% CI, 9.5-15.9) and 8.5 (95% CI, 6.5-11.2), respectively; for cases with ID ASD, these ORs were 6.4 (95% CI, 4.2-9.8) and 2.0 (95% CI, 1.0-3.9), respectively. The ORs for NAPD and BD for the nonautistic full siblings of cases for whom ASD was registered before age 16 years, adjusted for hearing loss, were 1.8 (95% CI, 1.1-2.7) and 1.7 (95% CI, 1.1-2.6), respectively. CONCLUSIONS AND RELEVANCE A diagnosis of ASD is associated with a substantially increased risk for NAPD and BD. This finding contributes to our understanding of these disorders and has implications for the management of ASD.

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A Population-Based Study of Shared Genetic Variation Between Premorbid IQ and Psychosis Among Male Twin Pairs and Sibling Pairs From Sweden

Cited by 52 publications

References 36 publications

Schizophrenia genetic variants are not associated with intelligence

Schizophrenia genetic variants are not associated with intelligence

Differential Effects of Common Variants inSCN2Aon General Cognitive Ability, Brain Physiology, and messenger RNA Expression in Schizophrenia Cases and Control Individuals

Risks for Nonaffective Psychotic Disorder and Bipolar Disorder in Young People With Autism Spectrum Disorder

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