Cohort profile: The Cohorts Consortium of Latin America and the Caribbean (CC-LAC)

Why was the cohort set up? Latin America and the Caribbean (LAC) are characterized by much diversity in terms of socio-economic status, ecology, environment, access to health care,1,2 as well as the frequency of risk factors for and prevalence or incidence of non-communicable diseases;3–7 importantly, these differences are observed both between and within countries in LAC.8,9 LAC countries share a large burden of non-communicable (e.g. diabetes and hypertension) and cardiovascular (e.g. ischaemic heart disease) diseases, with these conditions standing as the leading causes of morbidity, disability and mortality in most of LAC.10–12 These epidemiological estimates—e.g. morbidity—cannot inform about risk factors or risk prediction, which are relevant to identify prevention avenues. Cohort studies, on the other hand, could provide this evidence. Pooled analysis, using data from multiple cohort studies, have additional strengths such as increased statistical power and decreased statistical uncertainty.13 LAC cohort studies have been under-represented,14 or not included at all,15–17 in international efforts aimed at pooling data from multiple cohort studies. We therefore set out to pool data from LAC cohorts to address research questions that individual cohort studies would not be able to answer. Drawing from previous successful regional enterprises (e.g. Asia Pacific Cohort Studies Collaboration),18,19 we established the Cohorts Consortium of Latin America and the Caribbean (CC-LAC). The main aim of the CC-LAC is to start a collaborative cohort data pooling in LAC to examine the association between cardio-metabolic risk factors (e.g. blood pressure, glucose and lipids) and non-fatal and fatal cardiovascular outcomes (e.g. stroke or myocardial infarction). In so doing, we aim to provide regional risk estimates to inform disease burden metrics, as well as other ambitious projects including a cardiovascular risk score to strengthen cardiovascular prevention in LAC. Initial funding has been provided by a fellowship from the Wellcome Trust Centre for Global Health Research at Imperial College London (Strategic Award, Wellcome Trust–Imperial College Centre for Global Health Research, 100693/Z/12/Z). Additional funding is being provided by an International Training Fellowship from the Wellcome Trust (214185/Z/18/Z). At the time of writing, the daily operations and pooled database are hosted at Imperial College London, though a mid-term goal is to transfer this expertise and operations to LAC. The collaboration relies fundamentally on a strong regional network of health researchers and practitioner

Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study.

BACKGROUND: C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal. METHODS AND FINDINGS: We performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed. The strengths (F-statistics) of the IVs were 31.92-3,761.29 and 82.32-9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p < 0.001). We validated this finding with individual-level genotype data from the schizophrenia GWAS (OR 0.96 [95% CI 0.94-0.98]; p < 1.72 × 10-6). Further, we found that a standardized CRP polygenic risk score (CRPPRS) at p-value thresholds of 1 × 10-4, 0.001, 0.01, 0.05, and 0.1 using individual-level data also showed a protective effect (OR < 1.00) against schizophrenia; the first CRPPRS (built of SNPs with p < 1 × 10-4) showed a statistically significant (p < 2.45 × 10-4) protective effect with an OR of 0.97 (95% CI 0.95-0.99). The CRP GRSGWAS showed that a 10% increase in genetically determined CRP level was significantly associated with coronary artery disease (OR 0.88 [95% CI 0.84-0.94]; p < 2.4 × 10-5) and was nominally associated with the risk of inflammatory bowel disease (OR 0.85 [95% CI 0.74-0.98]; p < 0.03), Crohn disease (OR 0.81 [95% CI 0.70-0.94]; p < 0.005), psoriatic arthritis (OR 1.36 [95% CI 1.00-1.84]; p < 0.049), knee osteoarthritis (OR 1.17 [95% CI 1.01-1.36]; p < 0.04), and bipolar disorder (OR 1.21 [95% CI 1.05-1.40]; p < 0.007) and with an increase of 0.72 (95% CI 0.11-1.34; p < 0.02) mm Hg in systolic blood pressure, 0.45 (95% CI 0.06-0.84; p < 0.02) mm Hg in diastolic blood pressure, 0.01 ml/min/1.73 m2 (95% CI 0.003-0.02; p < 0.005) in estimated glomerular filtration rate from serum creatinine, 0.01 g/dl (95% CI 0.0004-0.02; p < 0.04) in serum albumin level, and 0.03 g/dl (95% CI 0.008-0.05; p < 0.009) in serum protein level. However, after adjustment for heterogeneity, neither GRS showed a significant effect of CRP level (at p < 0.0016) on any of these outcomes, including coronary artery disease, nor on the other 20 complex outcomes studied. Our study has two potential limitations: the limited variance explained by our genetic instruments modeling CRP levels in blood and the unobserved bias introduced by the use of summary statistics in our MR analyses. CONCLUSIONS: Genetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed p < 0.05 using either GRSCRP or GRSGWAS-with persistence after correction for heterogeneity-for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes

Copy number variation in bipolar disorder.

Large (>100 kb), rare (500 kb) CNVs in BD compared with SZ, most notably for deletions >1 Mb (P=9 × 10(-4))

Do regional brain volumes and major depressive disorder share genetic architecture?:A study of Generation Scotland (<i>n</i>=19,762), UK Biobank (<i>n</i>=24,048) and the English Longitudinal Study of Ageing (<i>n</i>=5,766)

Major depressive disorder (MDD) is a heritable and highly debilitating condition. It is commonly associated with subcortical volumetric abnormalities, the most replicated of these being reduced hippocampal volume. Using the most recent published data from Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium's genome-wide association study of regional brain volume, we sought to test whether there is shared genetic architecture between seven subcortical brain volumes and intracranial volume (ICV) and MDD. We explored this using linkage disequilibrium score regression, polygenic risk scoring (PRS) techniques, Mendelian randomisation (MR) analysis and BUHMBOX. Utilising summary statistics from ENIGMA and Psychiatric Genomics Consortium, we demonstrated that hippocampal volume was positively genetically correlated with MDD (rG=0.46, P=0.02), although this did not survive multiple comparison testing. None of the other six brain regions studied were genetically correlated and amygdala volume heritability was too low for analysis. Using PRS analysis, no regional volumetric PRS demonstrated a significant association with MDD or recurrent MDD. MR analysis in hippocampal volume and MDD identified no causal association, however, BUHMBOX analysis identified genetic subgrouping in GS:SFHS MDD cases only (P=0.00281). In this study, we provide some evidence that hippocampal volume and MDD may share genetic architecture in a subgroup of individuals, albeit the genetic correlation did not survive multiple testing correction and genetic subgroup heterogeneity was not replicated. In contrast, we found no evidence to support a shared genetic architecture between MDD and other regional subcortical volumes or ICV

Homozygous microdeletion of exon 5 in ZNF277 in a girl with specific language impairment

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The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia

Molecular genetic analysis offers opportunities to advance our understanding of the nosological relationship between psychiatric diagnostic categories in general, and the mood and psychotic disorders in particular. Strong evidence (P=7.0 × 10−7) of association at the polymorphism rs1006737 (within CACNA1C, the gene encoding the α-1C subunit of the L-type voltage-gated calcium channel) with the risk of bipolar disorder (BD) has recently been reported in a meta-analysis of three genome-wide association studies of BD, including our BD sample (N=1868) studied within the Wellcome Trust Case Control Consortium. Here, we have used our UK case samples of recurrent major depression (N=1196) and schizophrenia (N=479) and UK non-psychiatric comparison groups (N=15316) to examine the spectrum of phenotypic effect of the bipolar risk allele at rs1006737. We found that the risk allele conferred increased risk for schizophrenia (P=0.034) and recurrent major depression (P=0.013) with similar effect sizes to those previously observed in BD (allelic odds ratio ∼1.15). Our findings are evidence of some degree of overlap in the biological underpinnings of susceptibility to mental illness across the clinical spectrum of mood and psychotic disorders, and show that at least some loci can have a relatively general effect on susceptibility to diagnostic categories, as currently defined. Our findings will contribute to a better understanding of the pathogenesis of major psychiatric illness, and such knowledge should be useful in providing an etiological rationale for shaping psychiatric nosology, which is currently reliant entirely on descriptive clinical data

Discovery of 42 genome-wide significant loci associated with dyslexia

Funding: EE, GA, BM, BSP, CF and SEF are supported by the Max Planck Society (Germany). The Chinese Reading Study was supported by grants from the National Natural Science Foundation of China Youth Project (Grant No. 61807023), the Youth Fund for Humanities and Social Sciences Research of the Ministry of Education (Grant No. 19YJC190023 and 17XJC190010), and the Natural Science Basic Research Plan in Shaanxi Province of China (Grant No. 2021JQ-309). SP is funded by the Royal Society.Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia.Publisher PDFPeer reviewe

Corrigendum to Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci

Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form’s Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ~15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10−15) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ~1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes

Identifying genetic differences between bipolar disorder and major depression through multiple GWAS.

Background; Accurate diagnosis of bipolar disorder (BD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A key reason is that the first manic episode is often preceded by a depressive one, making it difficult to distinguish BD from unipolar major depressive disorder (MDD). Aims; Here, we use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores that may aid early differential diagnosis. Methods; Based on individual genotypes from case-control cohorts of BD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful merging and quality control procedure. In a resulting cohort of 51,149 individuals (15,532 BD cases, 12,920 MDD cases and 22,697 controls), we perform a variety of GWAS and polygenic risk scores (PRS) analyses. Results; While our GWAS is not well-powered to identify genome-wide significant loci, we find significant SNP-heritability and demonstrate the ability of the resulting PRS to distinguish BD from MDD, including BD cases with depressive onset. We replicate our PRS findings, but not signals of individual loci in an independent Danish cohort (iPSYCH 2015 case-cohort study, N=25,966). We observe strong genetic correlation between our case-case GWAS and that of case-control BD. Conclusions; We find that MDD and BD, including BD with a depressive onset, are genetically distinct. Further, our findings support the hypothesis that Controls – MDD — BD primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BD and, importantly, BD with depressive onset from MDD

Injury in China: a systematic review of injury surveillance studies conducted in Chinese hospital emergency departments

<p>Abstract</p> <p>Background</p> <p>Injuries represent a significant and growing public health concern in China. This <it>Review </it>was conducted to document the characteristics of injured patients presenting to the emergency department of Chinese hospitals and to assess of the nature of information collected and reported in published surveillance studies.</p> <p>Methods</p> <p>A systematic search of MEDLINE and China Academic Journals supplemented with a hand search of journals was performed. Studies published in the period 1997 to 2007 were included and research published in Chinese was the focus. Search terms included emergency, injury, medical care.</p> <p>Results</p> <p>Of the 268 studies identified, 13 were injury surveillance studies set in the emergency department. Nine were collaborative studies of which eight were prospective studies. Of the five single centre studies only one was of a prospective design. Transport, falls and industrial injuries were common mechanisms of injury. Study strengths were large patient sample sizes and for the collaborative studies a large number of participating hospitals. There was however limited use of internationally recognised injury classification and severity coding indices.</p> <p>Conclusion</p> <p>Despite the limited number of studies identified, the scope of each highlights the willingness and the capacity to conduct surveillance studies in the emergency department. This <it>Review </it>highlights the need for the adoption of standardized injury coding indices in the collection and reporting of patient health data. While high level injury surveillance systems focus on population-based priority setting, this <it>Review </it>demonstrates the need to establish an internationally comparable trauma registry that would permit monitoring of the trauma system and would by extension facilitate the optimal care of the injured patient through the development of informed quality assurance programs and the implementation of evidence-based health policy.</p