Building national patient registries in Mexico: insights from the MexOMICS Consortium.

Objective: To introduce MexOMICS, a Mexican Consortium focused on establishing electronic databases to collect, cross-reference, and share health-related and omics data on the Mexican population. Methods: Since 2019, the MexOMICS Consortium has established three electronic-based registries: the Mexican Twin Registry (TwinsMX), Mexican Lupus Registry (LupusRGMX), and the Mexican Parkinson's Research Network (MEX-PD), designed and implemented using the Research Electronic Data Capture web-based application. Participants were enrolled through voluntary participation and on-site engagement with medical specialists. We also acquired DNA samples and Magnetic Resonance Imaging scans in subsets of participants. Results: The registries have successfully enrolled a large number of participants from a variety of regions within Mexico: TwinsMX (n = 2,915), LupusRGMX (n = 1,761) and MEX-PD (n = 750). In addition to sociodemographic, psychosocial, and clinical data, MexOMICS has collected DNA samples to study the genetic biomarkers across the three registries. Cognitive function has been assessed with the Montreal Cognitive Assessment in a subset of 376 MEX-PD participants. Furthermore, a subset of 267 twins have participated in cognitive evaluations with the Creyos platform and in MRI sessions acquiring structural, functional, and spectroscopy brain imaging; comparable evaluations are planned for LupusRGMX and MEX-PD. Conclusions: The MexOMICS registries offer a valuable repository of information concerning the potential interplay of genetic and environmental factors in health conditions among the Mexican population.

TwinsMX: Exploring the Genetic and Environmental Influences on Health Traits in the Mexican Population.

TwinsMX registry is a national research initiative in Mexico that aims to understand the complex interplay between genetics and environment in shaping physical and mental health traits among the country's population. With a multidisciplinary approach, TwinsMX aims to advance our knowledge of the genetic and environmental mechanisms underlying ethnic variations in complex traits and diseases, including behavioral, psychometric, anthropometric, metabolic, cardiovascular and mental disorders. With information gathered from over 2800 twins, this article updates the prevalence of several complex traits; and describes the advances and novel ideas we have implemented such as magnetic resonance imaging. The future expansion of the TwinsMX registry will enhance our comprehension of the intricate interplay between genetics and environment in shaping health and disease in the Mexican population. Overall, this report describes the progress in the building of a solid database that will allow the study of complex traits in the Mexican population, valuable not only for our consortium, but also for the worldwide scientific community, by providing new insights of understudied genetically admixed populations.

Impact of genetic predisposition to late-onset neurodegenerative diseases on early life outcomes and brain structure.

Most patients with late-onset neurodegenerative diseases such as Alzheimer's and Parkinson's have a complex aetiology resulting from numerous genetic risk variants of small effects located across the genome, environmental factors, and the interaction between genes and environment. Over the last decade, genome-wide association studies (GWAS) and post-GWAS analyses have shed light on the polygenic architecture of these diseases, enabling polygenic risk scores (PRS) to estimate an individual's relative genetic liability for presenting with the disease. PRS can screen and stratify individuals based on their genetic risk, potentially years or even decades before the onset of clinical symptoms. An emerging body of evidence from various research studies suggests that genetic susceptibility to late-onset neurodegenerative diseases might impact early life outcomes, including cognitive function, brain structure and function, and behaviour. This article summarises recent findings exploring the potential impact of genetic susceptibility to neurodegenerative diseases on early life outcomes. A better understanding of the impact of genetic susceptibility to neurodegenerative diseases early in life could be valuable in disease screening, detection, and prevention and in informing treatment strategies before significant neural damage has occurred. However, ongoing studies have limitations. Overall, our review found several studies focused on APOE haplotypes and Alzheimer's risk, but a limited number of studies leveraging polygenic risk scores or focused on genetic susceptibility to other late-onset conditions.

Psychometric evaluation and linking of the PHQ-9, QIDS-C, and VQIDS-C in a real-world population with major depressive disorder.

Purpose: Major depressive disorder (MDD) is a leading cause of disability worldwide. An accurate assessment of depressive symptomology is crucial for clinical management and research. This study assessed the convergent validity, reliability, and total scale score interconversion across the 9-item Patient Health Questionnaire (PHQ-9) self-report, the 16-item Quick Inventory of Depressive Symptomatology-clinician report (QIDS-C) (two widely used clinical ratings) and the 5-item Very Brief Quick Inventory of Depressive Symptoms-clinician report (VQIDS-C), which evaluate the core features of MDD. Patients and Methods: This study leveraged electronic health record (EHR)-derived, de-identified data from the NeuroBlu Database (Version 23R1), a longitudinal behavioural health real-world platform. Classical Test Theory (CTT) and Item Response Theory (IRT) analyses were used to evaluate the reliability, validity of, and conversions between the scales. The Test Information Function (TIF) was calculated for each scale, with greater test information reflecting higher precision and reliability in measuring depressive symptomology. IRT was also used to generate conversion tables so that total scores on each scale could be compared to the other. Results: The study sample (n = 2,156) had an average age of 36.4 years (standard deviation [SD] = 13.0) and 59.7% were female. The mean depression scores for the PHQ-9, QIDS-C, and VQIDS-C were 12.9 (SD = 6.6), 12.0 (SD = 4.9), and 6.18 (SD = 3.2), respectively. The Cronbach's alpha coefficients for PHQ-9, QIDS-C, and VQIDS-C were 0.9, 0.8, and 0.7, respectively, suggesting acceptable internal consistency. PHQ-9 (TIF = 30.3) demonstrated the best assessment of depressive symptomology, followed by QIDS-C (TIF = 25.8) and VQIDS-C (TIF = 17.7). Conclusion: Overall, PHQ-9, QIDS-C, and VQIDS-C appear to be reliable and convertible measures of MDD symptomology within a US-based adult population in a real-world clinical setting.

Investigating the Shared Genetic Etiology Between Parkinson's Disease and Depression.

Background: Depression is a common symptom in Parkinson's disease (PD), resulting from underlying neuropathological processes and psychological factors. However, the extent to which shared genetic risk factors contribute to the relationship between depression and PD is poorly understood. Objective: To examine the effects of common genetic variants influencing the etiology of PD and depression risk at the genome-wide and local genomic regional level. Methods: We comprehensively investigated the genetic relationship between PD and depression using genome-wide association studies data. First, we estimated the genetic correlation at the genome-wide level using linkage-disequilibrium score regression, followed by local genetic correlation analysis using the GWAS-pairwise method and functional annotation to identify genes that may jointly influence the risk for both traits. Also, we performed Latent Causal Variable, Latent Heritable Confounder Mendelian Randomization, and traditional Mendelian Randomization analyses to investigate the potential causal relationship. Results: Although the genetic correlation between PD and depression was not statistically significant at the genome-wide level, GWAS-pairwise analyses identified 16 genomic segments associated with PD and depression, implicating nine genes. Further analyses revealed distinct patterns within individual genes, suggesting an intricate pattern. These genes involve various biological processes, including neurotransmitter regulation, senescence, and nucleo-cytoplasmic transport mechanisms. We did not observe genetic evidence of causality between PD and depression. Conclusions: Our findings did not support a genome-wide genetic correlation or a causal association between both conditions. However, we identified genomic segments but identified genomic segments linked to distinct biological pathways influencing their etiology.Further research is needed to understand their functional consequences.

Associations of externalizing polygenic scores with externalizing disorders among Mexican youth.

Several studies have examined the association of externalizing polygenic scores (PGS) with externalizing symptoms in samples of European ancestry. However, less is known about the associations of externalizing polygenic vulnerability in relation to phenotypic externalizing disorders among individuals of different ancestries, such as Mexican youth. Here, we leveraged the largest genome-wide association study on externalizing behaviors that included over 1 million individuals of European ancestry to examine associations of externalizing PGS with a range of externalizing disorders in Mexican adolescents, and investigated whether adversity exposure in childhood moderated these associations. Participants (N = 1064; age range 12-17 years old; 58.8% female) were adolescents recruited for a general population survey on adolescent mental health in the Mexico City Metropolitan region and were genotyped. Childhood adversity exposure and externalizing disorders, specifically attention-deficit hyperactivity disorder (ADHD), conduct disorder, oppositional defiant disorder, and substance use disorder, were assessed via the computer-assisted World Mental Health Composite International Diagnostic Interview for adolescents. A greater externalizing PGS was associated with a greater odds of any externalizing disorder (OR = 1.29 [1.12, 1.48]; p < 0.01) and ADHD (OR = 1.40 [1.15, 1.70]; p < 0.01) in the whole sample, and in females in particular. There were no main effects of the externalizing PGS on conduct disorder, oppositional defiant disorder, or substance use disorder, nor did adversity exposure moderate these associations. Our results suggest that greater genetic propensity for externalizing disorders is associated with increased odds of any externalizing disorders and ADHD among Mexican adolescents, furthering our understanding of externalizing disorder manifestation in this population.

Cross-national comparisons of later-life cognitive function using data from the Harmonized Cognitive Assessment Protocol (HCAP): Considerations and recommended best practices.

The Harmonized Cognitive Assessment Protocol (HCAP) is a major innovation that provides, for the first time, harmonized data for cross-national comparisons of later-life cognitive functions that are sensitive to linguistic, cultural, and educational differences across countries. However, cognitive function does not lend itself to direct comparison across diverse populations without careful consideration of the best practices for such comparisons. This perspective discusses theoretical and methodological considerations and offers a set of recommended best practices for conducting cross-national comparisons of risk factor associations using HCAP data. Because existing and planned HCAP studies provide cognition data representing an estimated 75% of the global population ≥65 years of age, these recommended best practices will support high-quality comparative analyses of cognitive aging around the world. The principles described in this perspective are applicable to any researcher aiming to integrate or compare harmonized data on cognitive outcomes and their risk and protective factors across diverse populations.

Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference.

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.

Fructose intake from sugar-sweetened beverages is associated with a greater risk of hyperandrogenism in women: UK Biobank cohort study.

OBJECTIVE: To assess the association between fructose consumption and serum sex hormone-binding globulin (SHBG), (free) testosterone, and risk of hyperandrogenism in a population-based cohort. DESIGN: An observational and genetic association study in participants of the UK Biobank (n = 136 384 and n = 383 392, respectively). METHODS: We assessed the relationship of (1) the intake of different sources of fructose (ie, total, fruit, fruit juice, and sugar-sweetened beverages [SSBs]) and (2) rs2304681 (a missense variant in the gene encoding ketohexokinase, used as an instrument of impaired fructose metabolism), with SHBG, total and free testosterone levels, and risk of hyperandrogenism (free androgen index >4.5). RESULTS: The intake of total fructose and fructose from fruit was associated with higher serum SHBG and lower free testosterone in men and women and lower risk of hyperandrogenism in women. In contrast, fructose intake from SSB (≥10 g/day) was associated with lower SHBG in men and women and with higher free testosterone levels and risk of hyperandrogenism in women (odds ratio [OR]: 1.018; 95% confidence interval [CI]: 1.010; 1.026). Carriers of the rs2304681 A allele were characterized by higher circulating SHBG (both men and women), lower serum free testosterone (women), and a lower risk of biochemical hyperandrogenism (OR: 0.997, 95% CI: 0.955; 0.999; women) and acne vulgaris (OR: 0.975, 95% CI: 0.952; 0.999; men and women combined). CONCLUSIONS: The consumption of ≥10 g/day fructose from SSB, corresponding to ≥200 mL serving, is associated with a 2% higher risk of hyperandrogenism in women. These observational data are supported by our genetic data.

Genome-wide association study meta-analysis of dizygotic twinning illuminates genetic regulation of female fecundity.

STUDY QUESTION: Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins? SUMMARY ANSWER: We identified four new loci, GNRH1, FSHR, ZFPM1, and IPO8, in addition to previously identified loci, FSHB and SMAD3. WHAT IS KNOWN ALREADY: The propensity to give birth to DZ twins runs in families. Earlier, we reported that FSHB and SMAD3 as associated with DZ twinning and female fertility measures. STUDY DESIGN, SIZE, DURATION: We conducted a genome-wide association meta-analysis (GWAMA) of mothers of spontaneous dizygotic (DZ) twins (8265 cases, 264 567 controls) and of independent DZ twin offspring (26 252 cases, 417 433 controls). PARTICIPANTS/MATERIALS, SETTING, METHODS: Over 700 000 mothers of DZ twins, twin individuals and singletons from large cohorts in Australia/New Zealand, Europe, and the USA were carefully screened to exclude twins born after use of ARTs. Genetic association analyses by cohort were followed by meta-analysis, phenome wide association studies (PheWAS), in silico and in vivo annotations, and Zebrafish functional validation. MAIN RESULTS AND THE ROLE OF CHANCE: This study enlarges the sample size considerably from previous efforts, finding four genome-wide significant loci, including two novel signals and a further two novel genes that are implicated by gene level enrichment analyses. The novel loci, GNRH1 and FSHR, have well-established roles in female reproduction whereas ZFPM1 and IPO8 have not previously been implicated in female fertility. We found significant genetic correlations with multiple aspects of female reproduction and body size as well as evidence for significant selection against DZ twinning during human evolution. The 26 top single nucleotide polymorphisms (SNPs) from our GWAMA in European-origin participants weakly predicted the crude twinning rates in 47 non-European populations (r = 0.23 between risk score and population prevalence, s.e. 0.11, 1-tail P = 0.058) indicating that genome-wide association studies (GWAS) are needed in African and Asian populations to explore the causes of their respectively high and low DZ twinning rates. In vivo functional tests in zebrafish for IPO8 validated its essential role in female, but not male, fertility. In most regions, risk SNPs linked to known expression quantitative trait loci (eQTLs). Top SNPs were associated with in vivo reproductive hormone levels with the top pathways including hormone ligand binding receptors and the ovulation cycle. LARGE SCALE DATA: The full DZT GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). LIMITATIONS, REASONS FOR CAUTION: Our study only included European ancestry cohorts. Inclusion of data from Africa (with the highest twining rate) and Asia (with the lowest rate) would illuminate further the biology of twinning and female fertility. WIDER IMPLICATIONS OF THE FINDINGS: About one in 40 babies born in the world is a twin and there is much speculation on why twinning runs in families. We hope our results will inform investigations of ovarian response in new and existing ARTs and the causes of female infertility. STUDY FUNDING/COMPETING INTEREST(S): Support for the Netherlands Twin Register came from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organization for Health Research and Development (ZonMW) grants, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI.NL, 184.021.007), Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB, European Research Council (ERC-230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1) and the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951. The QIMR Berghofer Medical Research Institute (QIMR) study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 1050208, 1075175). L.Y. is funded by Australian Research Council (Grant number DE200100425). The Minnesota Center for Twin and Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886) and the National Institute on Drug Abuse (DA05147, DA13240, and DA024417). The Women's Genome Health Study (WGHS) was funded by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with support for genotyping provided by Amgen. Data collection in the Finnish Twin Registry has been supported by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, AA-09203, AA15416, and K02AA018755) and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073 and 336823 to J. Kaprio). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. For NESDA, funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10000-1002), the Center for Medical Systems Biology (CSMB, NVVO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, ROI D0042157-01A, MH081802, Grand Opportunity grants 1 RC2 Ml-1089951 and IRC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. Work in the Del Bene lab was supported by the Programme Investissements d'Avenir IHU FOReSIGHT (ANR-18-IAHU-01). C.R. was supported by an EU Horizon 2020 Marie Sklodowska-Curie Action fellowship (H2020-MSCA-IF-2014 #661527). H.S. and K.S. are employees of deCODE Genetics/Amgen. The other authors declare no competing financial interests. TRIAL REGISTRATION NUMBER: N/A.

Neurocognitive, Sociocultural, and Psychological Factors Impacting Medication Beliefs Among HIV-Seropositive Latinx Adults.

Among Latinx people living with HIV (PLWH), neurocognitive (NC) function, culture, and mental health impact medication adherence. Similarly, health beliefs and attitudes play a role in health care barriers and health behaviors. Research has not examined the effect that compromised neurocognition, sociocultural factors, and mental health have on health beliefs and attitudes. This is especially relevant for Latinx PLWH who are disproportionately impacted by HIV, given that sociocultural factors may uniquely impact HIV-related NC and psychological sequelae. This study investigated the associations between neurocognition, sociocultural factors, mental health, health beliefs, and health attitudes among Latinx HIV-seropositive adults. Within a sample of 100 Latinx PLWH, better verbal learning and executive functioning abilities were associated with more positive attitudes about the benefits of medications and memory for medications. In terms of sociocultural factors, higher English language competence was related to better self-reported memory for medications, and overall, higher US acculturation was associated with more positive attitudes toward health professionals. Depressive symptomatology was negatively associated with attitudes toward medications and health professionals, as well as with self-reported memory for medications. These findings highlight the important interplay between NC, sociocultural, psychological factors, and health beliefs among Latinx PLWH. Adherence intervention strategies and suggestions for dispensing medical information are presented for clinicians and health care practitioners.

Discontinuation of antidepressant treatment: a retrospective cohort study on more than 20,000 participants.

BACKGROUND: Factors influencing antidepressant treatment discontinuation are poorly understood. In the present study, we aimed to estimate the prevalence of antidepressant treatment discontinuation and identify demographic characteristics, psychiatric comorbidities, and specific side effects associated with treatment discontinuation. METHODS: We leveraged data from the Australian Genetics of Depression Study (AGDS; N = 20,941) to perform a retrospective cohort study on antidepressant treatment discontinuation. Participants were eligible if they were over 18 years of age, had taken antidepressants in the past 4 years, and provided informed consent. RESULTS: Among the ten antidepressants studied, the highest discontinuation rates were observed for Mirtazapine (57.3%) and Amitriptyline (51.6%). Discontinuation rates were comparable across sexes except for Mirtazapine, for which women were more likely to discontinue. The two most common side effects, reduced sexual function and weight gain, were not associated with increased odds of treatment discontinuation. Anxiety, agitation, suicidal thoughts, vomiting, and rashes were associated with higher odds for treatment discontinuation, as were lifetime diagnoses of PTSD, ADHD, and a higher neuroticism score. Educational attainment showed a negative (protective) association with discontinuation across medications. CONCLUSIONS: Our study suggests that not all side effects contribute equally to discontinuation. Common side effects such as reduced sexual function and weight gain may not necessarily increase the risk of treatment discontinuation. Side effects linked to discontinuation can be divided into two groups, psychopathology related and allergy/intolerance.

WITHDRAWN: Genome-wide risk prediction of primary open-angle glaucoma across multiple ancestries.

This manuscript has been withdrawn by medRxiv following a formal request by the QIMR Berghofer Medical Research Institute Research Integrity Office owing to lack of author consent.

GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. CONCLUSIONS: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.

Harmonisation of later-life cognitive function across national contexts: results from the Harmonized Cognitive Assessment Protocols.

BACKGROUND: The Harmonized Cognitive Assessment Protocol (HCAP) is an innovative instrument for cross-national comparisons of later-life cognitive function, yet its suitability across diverse populations is unknown. We aimed to harmonise general and domain-specific cognitive scores from HCAP studies across six countries, and evaluate reliability and criterion validity of the resulting harmonised scores. METHODS: We statistically harmonised general and domain-specific cognitive function scores across publicly available HCAP partner studies in China, England, India, Mexico, South Africa, and the USA conducted between October, 2015 and January, 2020. Participants missing all cognitive test items in a given HCAP were excluded. We used an item banking approach that leveraged common cognitive test items across studies and tests that were unique to studies. We generated harmonised factor scores to represent a person's relative functioning on the latent factors of general cognitive function, memory, executive function, orientation, and language using confirmatory factor analysis. We evaluated the marginal reliability, or precision, of the factor scores using test information plots. Criterion validity of factor scores was assessed by regressing the scores on age, gender, and educational attainment in a multivariable analysis adjusted for these characteristics. FINDINGS: We included 21 144 participants from the six HCAP studies of interest (11 480 women [54·3%] and 9664 [45·7%] men), with a median age of 69 years (IQR 64-76). Confirmatory factor analysis models of cognitive function in each country fit well: 31 (88·6%) of 35 models had adequate or good fit to the data (comparative fit index ≥0·90, root mean square error of approximation ≤0·08, and standardised root mean residual ≤0·08). Marginal reliability of the harmonised general cognitive function factor was high (>0·9) for 19 044 (90·1%) of 21 144 participant scores across the six countries. Marginal reliability of the harmonised factor was above 0·85 for 19 281 (91·2%) of 21 142 participant factor scores for memory, 7805 (41·0%) of 19 015 scores for executive function, 3446 (16·3%) of 21 103 scores for orientation, and 4329 (20·5%) of 21 113 scores for language. In each country, general cognitive function scores were lower with older age and higher with greater levels of educational attainment. INTERPRETATION: We statistically harmonised cognitive function measures across six large population-based studies of cognitive ageing. These harmonised cognitive function scores empirically reflect comparable domains of cognitive function among older adults across the six countries, have high reliability, and are useful for population-based research. This work provides a foundation for international networks of researchers to make improved inferences and direct comparisons of cross-national associations of risk factors for cognitive outcomes in pooled analyses. FUNDING: US National Institute on Aging.

Estimating the Genetic Contribution to Astigmatism and Myopia in the Mexican Population.

Astigmatism and myopia are two common ocular refractive errors that can impact daily life, including learning and productivity. Current knowledge suggests that the etiology of these conditions is the result of a complex interplay between genetic and environmental factors. Studies in populations of European ancestry have demonstrated a higher concordance of refractive errors in monozygotic (MZ) twins compared to dizygotic (DZ) twins. However, there is a lack of studies on genetically informative samples of multi-ethnic ancestry. This study aimed to estimate the genetic contribution to astigmatism and myopia in the Mexican population. A sample of 1399 families, including 243 twin pairs and 1156 single twins, completed a medical questionnaire about their own and their co-twin's diagnosis of astigmatism and myopia. Concordance rates for astigmatism and myopia were estimated, and heritability and genetic correlations were determined using a bivariate ACE Cholesky decomposition method, decomposed into A (additive genetic), C (shared environmental) and E (unique environmental) components. The results showed a higher concordance rate for astigmatism and myopia for MZ twins (.74 and .74, respectively) than for DZ twins (.50 and .55). The AE model, instead of the ACE model, best fitted the data. Based on this, heritability estimates were .81 for astigmatism and .81 for myopia, with a cross-trait genetic correlation of rA = .80, nonshared environmental correlation rE = .89, and a phenotypic correlation of rP = .80. These results are consistent with previous findings in other populations, providing evidence for a similar genetic architecture of these conditions in the multi-ethnic Mexican population.

Associations of comorbid substance use disorders with clinical outcomes in schizophrenia using electronic health record data.

BACKGROUND AND HYPOTHESIS: Schizophrenia and comorbid substance use disorders (SUDs) are associated with poor treatment outcomes but differences between the associations of different SUDs with clinical outcomes are poorly characterized. This study examines the associations of comorbid SUDs with clinical outcomes in schizophrenia using a largescale electronic health record (EHR) database. DESIGN: Real-world data (RWD) analysis using the NeuroBlu database; de-identified EHR data were analysed. Multivariable logistic regression, Poisson and CoxPH models were used to compare the associations of specific comorbid SUDs with outcome variables. RESULTS: Comorbid SUD was significantly different on all outcome measures compared to no SUD (U = 1.44e7-1.81e7, all ps < .001), except number of unique antipsychotics (U = 1.61e7, p = .43). Cannabis (OR = 1.58, p < .001) and polysubstance (OR = 1.22, p = .007) use disorders were associated with greater CGI-S. Cannabis (IRR = 1.13, p = .003) and polysubstance (IRR = 1.08, p = .003) use disorders were associated with greater number of unique antipsychotics prescribed, while cocaine (HR = 1.87, p < .001), stimulants (HR = 1.64, p = .024), and polysubstance (HR = 1.46, p < .001) use disorders were associated with a shorter time to antipsychotic discontinuation. Conversely, alcohol use (IRR = 0.83, p < .001), cocaine use (IRR = 0.61, p < .001), opioid use (IRR = 0.61, p < .001), stimulant use (IRR = 0.57, p < .001) and polysubstance use (IRR = 0.87, p < .001) disorders were associated fewer inpatient days. CONCLUSION: Comorbid SUDs were generally associated with greater CGI-S and poorer clinical outcomes in patients with schizophrenia. Treatment strategies should target not only schizophrenia symptoms but also comorbid SUD to improve management of both conditions.

Memory and language cognitive data harmonization across the United States and Mexico.

INTRODUCTION: We used cultural neuropsychology-informed procedures to derive and validate harmonized scores representing memory and language across population-based studies in the United States and Mexico. METHODS: Data were from the Health and Retirement Study Harmonized Cognitive Assessment Protocol (HRS-HCAP) and the Mexican Health and Aging Study (MHAS) Ancillary Study on Cognitive Aging (Mex-Cog). We statistically co-calibrated memory and language domains and performed differential item functioning (DIF) analysis using a cultural neuropsychological approach. We examined relationships among harmonized scores, age, and education. RESULTS: We included 3170 participants from the HRS-HCAP (Mage = 76.6 [standard deviation (SD): 7.5], 60% female) and 2042 participants from the Mex-Cog (Mage = 68.1 [SD: 9.0], 59% female). Five of seven memory items and one of twelve language items demonstrated DIF by study. Harmonized memory and language scores showed expected associations with age and education. DISCUSSION: A cultural neuropsychological approach to harmonization facilitates the generation of harmonized measures of memory and language function in cross-national studies. HIGHLIGHTS: We harmonized memory and language scores across studies in the United States and Mexico.A cultural neuropsychological approach to data harmonization was used.Harmonized scores showed minimal measurement differences between cohorts.Future work can use these harmonized scores for cross-national studies of Alzheimer's disease and related dementias.

MEX-PD: A National Network for the Epidemiological & Genetic Research of Parkinson's Disease.

Background: Parkinson's Disease (PD) has a complex etiology, involving genetic and environmental factors. Most of our current understanding of the disease comes from studies in populations with mostly European ancestry, representing challenges in generalizing findings to other populations with different genetic, social, and environmental contexts. There are scarce studies focused in Latin American populations. The Mexican population is genetically diverse because its admixture from Native American, European, and African ancestries, coupled with the unique environmental conditions, stressing the relevance of establishing genetic studies in this population. Thus, we have established the Mexican Parkinson's Research Network (MEX-PD), a consortium to research the clinical, genetical, environmental, and neurophysiological bases of the phenotypic diversity in Mexican PD patients. Objectives: Describing how MEX-PD was established, the methods and instruments and presenting the first results. Methods: Patients and controls were recruited from medical centers in 20 states of Mexico. Initial recruitment included neurological evaluation, cognitive assessment, and DNA collection. Results: MEX-PD has registered 302 controls and 262 PD patients with a mean age of diagnosis of 61 years (SD=10.86). There were 19.8% PD patients identified with early onset. Levodopa was the most common pharmacological treatment. Conclusions: MEX-PD contributes to understand PD nationally. The information gathered here will allow us to understand the prevalence of mental health, neurological symptoms, and cognitive function in the PD Mexican population and how genetical and environmental factors contributes to those outcomes. These will advocate for personalized treatments and improving quality of life in the Mexican population.