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

ABSTRACT: 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.

SUBMITTER: Trampush JW

PROVIDER: S-EPMC5322272 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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

Trampush J W JW Yang M L Z ML Yu J J Knowles E E Davies G G Liewald D C DC Starr J M JM Djurovic S S Melle I I Sundet K K Christoforou A A Reinvang I I DeRosse P P Lundervold A J AJ Steen V M VM Espeseth T T Räikkönen K K Widen E E Palotie A A Eriksson J G JG Giegling I I Konte B B Roussos P P Giakoumaki S S Burdick K E KE Payton A A Ollier W W Horan M M Chiba-Falek O O Attix D K DK Need A C AC Cirulli E T ET Voineskos A N AN Stefanis N C NC Avramopoulos D D Hatzimanolis A A Arking D E DE Smyrnis N N Bilder R M RM Freimer N A NA Cannon T D TD London E E Poldrack R A RA Sabb F W FW Congdon E E Conley E D ED Scult M A MA Dickinson D D Straub R E RE Donohoe G G Morris D D Corvin A A Gill M M Hariri A R AR Weinberger D R DR Pendleton N N Bitsios P P Rujescu D D Lahti J J Le Hellard S S Keller M C MC Andreassen O A OA Deary I J IJ Glahn D C DC Malhotra A K AK Lencz T T

Molecular psychiatry 20170117 3

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 acr ...[more]

PMID: 28093568

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Project description:ImportanceSchizophrenia is associated with widespread cognitive impairments. Although cognitive deficits are one of the factors most strongly associated with functional outcome in schizophrenia, current treatment strategies largely fail to ameliorate these impairments. To develop more efficient treatment strategies in patients with schizophrenia, a better understanding of the pathogenesis of these cognitive deficits is needed. Accumulating evidence indicates that genetic risk of schizophrenia may contribute to cognitive dysfunction.ObjectiveTo identify genomic regions jointly influencing schizophrenia and the cognitive domains of reaction time and verbal-numerical reasoning, as well as general cognitive function, a phenotype that captures the shared variation in performance across cognitive domains.Design, setting, and participantsCombining data from genome-wide association studies from multiple phenotypes using conditional false discovery rate analysis provides increased power to discover genetic variants and could elucidate shared molecular genetic mechanisms. Data from the following genome-wide association studies, published from July 24, 2014, to January 17, 2017, were combined: schizophrenia in the Psychiatric Genomics Consortium cohort (n = 79 757 [cases, 34 486; controls, 45 271]); verbal-numerical reasoning (n = 36 035) and reaction time (n = 111 483) in the UK Biobank cohort; and general cognitive function in CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) (n = 53 949) and COGENT (Cognitive Genomics Consortium) (n = 27 888).Main outcomes and measuresGenetic loci identified by conditional false discovery rate analysis. Brain messenger RNA expression and brain expression quantitative trait locus functionality were determined.ResultsAmong the participants in the genome-wide association studies, 21 loci jointly influencing schizophrenia and cognitive traits were identified: 2 loci shared between schizophrenia and verbal-numerical reasoning, 6 loci shared between schizophrenia and reaction time, and 14 loci shared between schizophrenia and general cognitive function. One locus was shared between schizophrenia and 2 cognitive traits and represented the strongest shared signal detected (nearest gene TCF20; chromosome 22q13.2), and was shared between schizophrenia (z score, 5.01; P = 5.53 × 10-7), general cognitive function (z score, -4.43; P = 9.42 × 10-6), and verbal-numerical reasoning (z score, -5.43; P = 5.64 × 10-8). For 18 loci, schizophrenia risk alleles were associated with poorer cognitive performance. The implicated genes are expressed in the developmental and adult human brain. Replicable expression quantitative trait locus functionality was identified for 4 loci in the adult human brain.Conclusions and relevanceThe discovered loci improve the understanding of the common genetic basis underlying schizophrenia and cognitive function, suggesting novel molecular genetic mechanisms.

Project description:BackgroundLiver disease is any condition that causes liver damage and inflammation and may likely affect the function of the liver. Vital biochemical screening tools that can be used to evaluate the health of the liver and help diagnose, prevent, monitor, and control the development of liver disease are known as liver function tests (LFT). LFTs are performed to estimate the level of liver biomarkers in the blood. Several factors are associated with differences in concentration levels of LFTs in individuals, such as genetic and environmental factors. The aim of our study was to identify genetic loci associated with liver biomarker levels with a shared genetic basis in continental Africans, using a multivariate genome-wide association study (GWAS) approach.MethodsWe used two distinct African populations, the Ugandan Genome Resource (UGR = 6,407) and South African Zulu cohort (SZC = 2,598). The six LFTs used in our analysis were: aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), total bilirubin, and albumin. A multivariate GWAS of LFTs was conducted using the exact linear mixed model (mvLMM) approach implemented in GEMMA and the resulting P-values were presented in Manhattan and quantile-quantile (QQ) plots. First, we attempted to replicate the findings of the UGR cohort in SZC. Secondly, given that the genetic architecture of UGR is different from that of SZC, we further undertook similar analysis in the SZC and discussed the results separately.ResultsA total of 59 SNPs reached genome-wide significance (P = 5x10-8) in the UGR cohort and with 13 SNPs successfully replicated in SZC. These included a novel lead SNP near the RHPN1 locus (lead SNP rs374279268, P-value = 4.79x10-9, Effect Allele Frequency (EAF) = 0.989) and a lead SNP at the RGS11 locus (lead SNP rs148110594, P-value = 2.34x10-8, EAF = 0.928). 17 SNPs were significant in the SZC, while all the SNPs fall within a signal on chromosome 2, rs1976391 mapped to UGT1A was identified as the lead SNP within this region.ConclusionsUsing multivariate GWAS method improves the power to detect novel genotype-phenotype associations for liver functions not found with the standard univariate GWAS in the same dataset.

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

Publications

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

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