The impact of rare protein coding genetic variation on adult cognitive function

Chen, Chia‐Yen; Tian, Ruoyu; Ge, Tian; Lam, Max; Sánchez-Andrade, Gabriela; Singh, Tarjinder; Urpa, Lea; Liu, Jiang; Sanderson, Mark; Rowley, Christine; Ironfield, Holly; Fang, Terry; Daly, Mark J.; Palotie, Aarno; Tsai, Ellen; Huang, Hailiang; Hurles, Matthew E.; Gerety, Sebastian S.; Lencz, Todd; Runz, Heiko

doi:10.1101/2022.06.24.22276728

Cited by 12 publications

(15 citation statements)

References 107 publications

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“…Cortical neural precursors differentiated from human iPSCs null for KPTN robustly support the mouse findings. We also identify a previously unrecognised effect of head overgrowth in heterozygous carriers of KPTN alleles, consistent with the recent studies showing that heterozygosity of alleles for other recessive disorders may be contributing to incompletely penetrant phenotypes in the general population 35–38 . Together, these models confirm KPTN to be among a growing list of mTOR modulating disease associated genes and provide a platform for further exploring the pathomechanistic basis of KRD.…”

Section: Introductionsupporting

confidence: 90%

“…While the role of somatic and germline mutations affecting mTOR signalling in pathological brain overgrowth is well established 25,100,101 , we were surprised to find such a strong, yet previously unrecognised phenotype effect of brain overgrowth in heterozygotes. There is increasing evidence of a role for recessive disease alleles in causing incompletely penetrant phenotypes in the general population, as the rapidly growing sequencing efforts provide the necessary power to detect these effects [35][36][37][38] . While KPTN heterozygotes are not known to experience any neurological consequences, constraint metrics such as LOEUF 102 indicate that KPTN LoF alleles may be experiencing purifying selection beyond what would be expected from a purely autosomal recessive disorder gene (observed/expected LoF=0.5, LOEUF=0.81).…”

Section: Discussionmentioning

confidence: 99%

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Mouse and cellular models of KPTN-related disorder implicate mTOR signalling in cognitive and progressive overgrowth phenotypes

Levitin

Rawlins

Sánchez-Andrade

et al. 2022

Preprint

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KPTN-related disorder (KRD) is an autosomal recessive disorder associated with germline variants in KPTN (kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KRD, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn-/- mice display many of the key KRD phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. Assessment of affected individuals has identified concordant selectivity of cognitive deficits, postnatal onset of brain overgrowth, and a previously unrecognised KPTN dosage-sensitivity, resulting in increased head circumference in their heterozygous parents. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape, and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated iPSC models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. Increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KRD in the broader group of mTORC1 related disorders affecting brain structure, cognitive function, and network integrity.

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Section: Introductionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Mouse and cellular models of KPTN-related disorder implicate mTOR signalling in cognitive and progressive overgrowth phenotypes

Levitin

Rawlins

Sánchez-Andrade

et al. 2022

Preprint

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“…Schizophrenia and cognitive ability in the general population are highly heritable and have partly overlapping polygenic architectures [10][11][12][13] . Thus, common genetic variant liability to schizophrenia is negatively correlated with that for higher IQ (with coe cients ranging between − 0.2 and − 0.4) 11 .…”

Section: Introductionmentioning

confidence: 99%

Family-based analysis of the contribution of rare and common genetic variants to school performance in schizophrenia

Rees

Kirov

Hubbard

et al. 2022

Preprint

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Impaired cognition in schizophrenia is associated with worse functional outcomes. While genetic factors are known to contribute to variation in cognition in schizophrenia, few rare coding variants with strong effects have been identified, and the relative effects from de novo, inherited and non-transmitted alleles are unknown. We used array and exome sequencing data from 656 proband-parent trios to examine the contribution of rare and common variants to school performance, and by implication cognitive function, in schizophrenia. Probands who performed worse at school were enriched for damaging de novo coding variants in genes associated with developmental disorders (DD) (p-value = 0.00026; OR = 11.6). Damaging, ultra-rare coding variants in DD genes that were transmitted or non-transmitted from parents, had no effects on school performance. 13 probands had damaging de novocoding variants in DD genes, of whom 12 had lower school performance. Among probands with lower school performance, those with damaging de novocoding variants in DD genes had a higher rate of comorbid mild intellectual disability (p-value = 0.0002; OR = 15.6). Parental transmission of common genetic liability for educational attainment and intelligence, but not for schizophrenia, was associated with proband school performance, but no significant effects were seen for non-transmitted parental alleles. Overall, we provide evidence for rare and common genetic contributions to school performance in schizophrenia. The strong effects for damaging de novocoding variants in DD genes provide further evidence that cognitive impairment in schizophrenia has a shared aetiology with developmental disorders. Furthermore, we report no evidence in this sample that non-transmitted parental alleles for cognitive traits contributed to school performance in schizophrenia via indirect effects on the environment.

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“…Schizophrenia and cognitive ability in the general population are highly heritable and have partly overlapping polygenic architectures [10][11][12][13]. Thus, common genetic liability to schizophrenia is negatively correlated with that for higher IQ (with coefficients ranging between −0.2 and −0.4) [11].…”

Section: Introductionmentioning

confidence: 99%

Family-based analysis of the contribution of rare and common genetic variants to school performance in schizophrenia

et al. 2023

View full text Add to dashboard Cite

Impaired cognition in schizophrenia is associated with worse functional outcomes. While genetic factors are known to contribute to variation in cognition in schizophrenia, few rare coding variants with strong effects have been identified, and the relative effects from de novo, inherited and non-transmitted alleles are unknown. We used array and exome sequencing data from 656 proband-parent trios to examine the contribution of common and rare variants to school performance, and by implication cognitive function, in schizophrenia. Parental transmission of common alleles contributing to higher educational attainment (p value = 0.00015; OR = 2.63) and intelligence (p value = 0.00009; OR = 2.80), but not to schizophrenia, were associated with higher proband school performance. No significant effects were seen for non-transmitted parental common alleles. Probands with lower school performance were enriched for damaging de novo coding variants in genes associated with developmental disorders (DD) (p value = 0.00026; OR = 11.6). Damaging, ultra-rare coding variants in DD genes that were transmitted or non-transmitted from parents, had no effects on school performance. Among probands with lower school performance, those with damaging de novo coding variants in DD genes had a higher rate of comorbid mild intellectual disability (p value = 0.0002; OR = 15.6). Overall, we provide evidence for rare and common genetic contributions to school performance in schizophrenia. The strong effects for damaging de novo coding variants in DD genes provide further evidence that cognitive impairment in schizophrenia has a shared aetiology with developmental disorders. Furthermore, we report no evidence in this sample that non-transmitted parental common alleles for cognitive traits contributed to school performance in schizophrenia via indirect effects on the environment.

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The impact of rare protein coding genetic variation on adult cognitive function

Cited by 12 publications

References 107 publications

Mouse and cellular models of KPTN-related disorder implicate mTOR signalling in cognitive and progressive overgrowth phenotypes

Mouse and cellular models of KPTN-related disorder implicate mTOR signalling in cognitive and progressive overgrowth phenotypes

Family-based analysis of the contribution of rare and common genetic variants to school performance in schizophrenia

Family-based analysis of the contribution of rare and common genetic variants to school performance in schizophrenia

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