GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

This corrects the article DOI: 10.1038/mp.2016.244.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

The relationship between temperament and character and psychotic-like experiences in healthy children and adolescents.

BACKGROUND: Prior work by our group identified personality profiles associated with psychotic-like experiences (PLE's) in healthy adults that were strikingly similar to those found in schizophrenia patients, with the exception of two key differences. Specifically, higher levels of PLE's were linked to higher persistence and cooperativeness, suggesting that these characteristics might represent personality-based resilience factors. Notably, age and personality were significantly correlated in these data, raising questions about whether healthy children and adolescents would show similar results. To date, no study has examined personality profiles associated with both positive and negative PLE's in healthy children and adolescents using Cloninger's Temperament and Character Inventory (TCI). Thus, this study examined the relationship between TCI dimensions and PLE's in healthy children and adolescents. METHOD: The TCI and the Community Assessment of Psychic Experiences (CAPE) were administered to 123 healthy children and adolescents aged 8-18. Multiple regression models were used to examine personality dimensions associated with overall severity of PLE's as well as severity of positive and negative PLE's separately. RESULTS: Positive, negative, and overall PLE severity were all associated with a personality pattern of higher harm avoidance and lower self-directedness. Negative PLE severity was also associated with lower persistence. CONCLUSIONS: Personality correlates of PLE's in healthy children and adolescents were largely consistent with our past work on PLE's in healthy adults. However, our previously identified resilience factors were notably absent in this sample. These findings may suggest that these personality characteristics have not yet crystallized or emerged to aid in coping with PLE's.

Genome-wide autozygosity is associated with lower general cognitive ability.

Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.

The relationship between temperament and character and subclinical psychotic-like experiences in healthy adults.

BACKGROUND: Considerable data support phenomenological and temporal continuity between psychotic disorders and subclinical psychotic-like experiences (PLE's). Although numerous studies have found similar personality correlates for schizophrenia and schizotypal personality disorder patients, their unaffected first-degree relatives, and healthy adults characterized for schizotypal traits, no study has yet investigated personality correlates of PLE's measured by the Community Assessment of Psychic Experiences (CAPE). Our study sought to examine personality correlates of PLE's using the CAPE in healthy adults. METHOD: The CAPE and temperament and character inventory (TCI) were administered to 415 healthy adults. Regressions examined links between TCI traits and overall PLE levels as well as positive and negative PLE's separately. RESULTS: Consistent with past studies, lower self-directedness (SD) and reward dependence (RD) and higher self-transcendence (ST) and harm avoidance (HA) significantly predicted overall PLE levels. Higher ST and persistence (P) and lower SD significantly predicted higher levels of positive PLE's while lower SD and RD and higher HA, ST, and cooperativeness (C) predicted higher levels of negative PLE's. CONCLUSIONS: Associations between TCI and PLE's using the CAPE are strikingly similar to past work in non-clinical and patient samples and provide additional support for phenomenological continuity between psychotic disorders and sub-syndromal psychotic symptoms.