Genome-wide approaches including polygenic risk scores (PRSs) are now widely used in medical research; however, few studies have been conducted in low- and middle-income countries (LMICs), especially in South America. This study was designed to test the transferability of psychiatric PRSs to individuals with different ancestral and cultural backgrounds and to provide genome-wide association study (GWAS) results for psychiatric outcomes in this sample. The PrOMIS cohort (N = 3308) was recruited from prenatal care clinics at the Instituto Nacional Materno Perinatal (INMP) in Lima, Peru. Three major psychiatric outcomes (depression, PTSD, and suicidal ideation and/or self-harm) were scored by interviewers using valid Spanish questionnaires. Illumina Multi-Ethnic Global chip was used for genotyping. Standard procedures for PRSs and GWAS were used along with extra steps to rule out confounding due to ancestry. Depression PRSs significantly predicted depression, PTSD, and suicidal ideation/self-harm and explained up to 0.6% of phenotypic variation (minimum p = 3.9 × 10−6). The associations were robust to sensitivity analyses using more homogeneous subgroups of participants and alternative choices of principal components. Successful polygenic prediction of three psychiatric phenotypes in this Peruvian cohort suggests that genetic influences on depression, PTSD, and suicidal ideation/self-harm are at least partially shared across global populations. These PRS and GWAS results from this large Peruvian cohort advance genetic research (and the potential for improved treatments) for diverse global populations. / National Institutes of Health / Revisión por pares

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Yes / Importance: Myopia is a leading cause of untreatable visual impairment and is increasing in prevalence worldwide. Interventions for slowing childhood myopia progression have shown success in randomized clinical trials; hence, there is a need to identify which children would benefit most from treatment intervention. Objectives: To examine whether genetic information alone can identify children at risk of myopia development and whether including a child’s genetic predisposition to educational attainment is associated with improved genetic prediction of the risk of myopia. Design, Setting, and Participants: Meta-analysis of 3 genome-wide association studies (GWAS) including a total of 711 984 individuals. These were a published GWAS for educational attainment and 2 GWAS for refractive error in the UK Biobank, which is a multisite cohort study that recruited participants between January 2006 and October 2010. A polygenic risk score was applied in a population-based validation sample examined between September 1998 and September 2000 (Avon Longitudinal Study of Parents and Children [ALSPAC] mothers). Data analysis was performed from February 2018 to May 2019. Main Outcomes and Measures: The primary outcome was the area under the receiver operating characteristic curve (AUROC) in analyses for predicting myopia, using noncycloplegic autorefraction measurements for myopia severity levels of less than or equal to −0.75 diopter (D) (any), less than or equal to -3.00 D (moderate), or less than or equal to −5.00 D (high). The predictor variable was a polygenic risk score (PRS) derived from genome-wide association study data for refractive error (n = 95 619), age of onset of spectacle wear (n = 287 448), and educational attainment (n = 328 917). Results: A total of 383 067 adults aged 40 to 69 years from the UK Biobank were included in the new GWAS analyses. The PRS was evaluated in 1516 adults aged 24 to 51 years from the ALSPAC mothers cohort. The PRS had an AUROC of 0.67 (95% CI, 0.65-0.70) for myopia, 0.75 (95% CI, 0.70-0.79) for moderate myopia, and 0.73 (95% CI, 0.66-0.80) for high myopia. Inclusion in the PRS of information associated with genetic predisposition to educational attainment marginally improved the AUROC for myopia (AUROC, 0.674 vs 0.668; P = .02), but not those for moderate and high myopia. Individuals with a PRS in the top 10% were at 6.1-fold higher risk (95% CI, 3.4–10.9) of high myopia. Conclusions and Relevance: A personalized medicine approach may be feasible for detecting very young children at risk of myopia. However, accuracy must improve further to merit uptake in clinical practice; currently, cycloplegic autorefraction remains a better indicator of myopia risk (AUROC, 0.87). / PhD studentship grant from the College of Optometrists (Drs Guggenheim and Williams; supporting Mr Mojarrad) entitled Genetic prediction of individuals at-risk for myopia development) and National Institute for Health Research (NIHR) Senior Research Fellowship award SRF-2015-08-005 (Dr Williams). The UK Medical Research Council and Wellcome grant 102215/2/13/2 and the University of Bristol provide core support for the Avon Longitudinal Study of Parents and Children (ALSPAC). A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). This research was conducted using the UK Biobank Resource (application 17351). The UK Biobank was established by the Wellcome Trust, the UK Medical Research Council, the Department for Health (London, England), the Scottish government (Edinburgh, Scotland), and the Northwest Regional Development Agency (Warrington, England). It also received funding from the Welsh Assembly Government (Cardiff, Wales), the British Heart Foundation, and Diabetes UK.

Yes / Background: Myopia has been shown to have a complex mode of inheritance, being influenced by both genetic and environmental factors. Here, an introduction into myopia genetics is given, with the shortcomings of current genetic prediction for myopia discussed, including the proportionally limited research on genetic prediction in people of non-European ancestry. A previously developed genetic risk score derived from European participants was evaluated in participants of non-European ancestry. Methods: Participants from UK Biobank who self-reported their ethnicity as “Asian”, “Chinese”, or “Black” and who had refractive error and genetic data available were included in the analysis. Ancestral homogeneity was confirmed using principal component analysis, resulting in samples of 3500 Asian, 444 Chinese, and 3132 Black participants. A published refractive error GWAS meta-analysis of 711,984 participants of European ancestry was used to create a weighted genetic risk score model which was then applied to participants from each ethnic group. Accuracy of genetic prediction of refractive error was estimated as the proportion of variance explained (PVE). Receiver operating characteristic (ROC) curves were developed to estimate myopia prediction performance at three thresholds: any myopia (equal to or more than 0.75D), moderate myopia (between -3.00D and -4.99D) and high myopia (equal to or more than -5.00D). Odds ratios for myopia were calculated for the participants in the top 10th or 5th percentile of genetic risk score distribution, comparing them to the remainder of the population. Results: The PVE value for refractive error was 6.4%, 6.2%, and 1.5% for those with Asian, Chinese and Black ethnicity, respectively (compared to 11.2% in Europeans). Odds ratios for any myopia and moderate myopia development for those within the top 10th and 5th percentile of genetic risk were significant in all ethnic groups P<0.05). However, the genetic risk score was not able to reliably identify those at risk of high myopia, other than for participants of Chinese ethnicity (P<0.05). Conclusion: Prediction of refractive error in Asian, Chinese and Black participants was ~57%, 55% and 13% as accurate in comparison to prediction in European participants. Further research in diverse ethnic populations is needed to improve prediction accuracy. / This research has been conducted using the UK Biobank Resource (applications #17351). UK Biobank was established by the Wellcome Trust; the UK Medical Research Council; the Department for Health (London, UK); Scottish Government (Edinburgh, UK); and the Northwest Regional Development Agency (Warrington, UK). It also received funding from the Welsh Assembly Government (Cardiff, UK); the British Heart Foundation; and Diabetes UK. Collection of eye and vision data was supported by The Department for Health through an award made by the NIHR to the Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, and UCL Institute of Ophthalmology, London, United Kingdom (grant no. BRC2_009). Additional support was provided by The Special Trustees of Moorfields Eye Hospital, London, United Kingdom (grant no. ST 12 09). Many parts of this project were performed during the time that author Neema Ghorbani Mojarrad was supported by the College of Optometrists with a Postgraduate Scholarship.

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Deficits in a number of cognitive domains have been associated with core symptoms of schizophrenia, including working memory, attention, motor skills, reaction time, episodic memory and executive function. Bipolar Disorder is also associated with cognitive impairment; however the level of impairment appears to be less severe than that seen in schizophrenia. A translocation (t(1;11)) containing the Disrupted-in-Schizophrenia 1 (DISC1) gene has been found to be highly associated with schizophrenia, bipolar disorder and major depressive disorder. As such, this gene has been the focus of much research and to date DISC1 has been found to be associated with brain development, brain structure and the glutamate system - all key factors in current models of schizophrenia and affective disorders. The aim of this PhD is to identify cognitive domains that are differentially impaired or unimpaired in a large Scottish family, some of whom carry this rare DISC1 variant, a balanced translocation (t (1;11) (q 42; q14.3)), that segregates with schizophrenia and affective disorders, as well as psychiatric patients with schizophrenia and bipolar disorder and healthy control subjects. All participants have undergone standardised cognitive assessments to measure premorbid I.Q. (NART), current I.Q. (WASI) verbal memory, working memory, verbal fluency, processing speed, motor skills, executive function (BACS) and selected CANTAB tasks to assess simple and five-choice reaction time. Polygenic risk profile scores and self-report questionnaire data have also been investigated. Results indicate an impact of the DISC1 t(1;11) translocation on general intelligence and attention and processing speed. Significant differences were also identified between DISC1 t(1;11) carriers and non-carriers on self-report questionnaire data. Mean scores for polygenic risk for bipolar disorder were significantly different between DISC1 t(1;11) carriers and non-carriers and polygenic risk for schizophrenia was significantly associated with symptom severity, as measured by the Positive and Negative Symptom Scale (PANSS). Within the patient groups, a measure of processing speed (the token motor task) was found to be significantly different between those with schizophrenia and bipolar disorder and there was also a trend for attention and processing speed. As expected, I.Q. was significantly different between patients and control participants. Clinical ratings were significantly associated with neuropsychological and self-report measures. Polygenic risk for major depressive disorder was found to be significantly associated with impaired general intelligence (current IQ) and slowed reaction time in patients who were not currently depressed, suggesting there may be genetic risk markers in this population which impact on cognition. This is a novel finding and further suggests the possibility of a biological component related to the genetics of depression. In conclusion, and in line with the literature, psychosis has a negative impact on cognition with reduced performance across several neuropsychological tasks between patient groups, with schizophrenia patients performing worse than patients with bipolar disorder and both patient groups performing worse than healthy control participants. Cognition is markedly more impaired in DISC1 t(1;11) translocation carriers and especially in those with psychosis. The DISC1 t(1;11) translocation and psychosis may therefore confer a “double hit” on cognition - in addition to psychosis itself - which is known to impair cognitive function, significantly increasing the level of cognitive impairment and increasing the risk for psychosis in general.

Alcohol use (AU) and alcohol use disorder (AUD) are leading causes of morbidity, premature death, and economic burden. They are also associated with high levels of disability and many other negative outcomes. Twin and family studies have consistently shown that AU and AUD are complex traits influenced by both genetic and environmental factors. Although much has been learned about the genetic and environmental etiology of AU and AUD, significant gaps remain. These include the need for a more comprehensive understanding of the roles of risk and protective factors, and the nature of developmental trajectories underpinning the progression from AU to AUD. The aims of this dissertation are: (1) to examine the roles of resilience and personality disorders in the etiology of AU and AUD; (2) to investigate the nature of longitudinal changes in genetic and environmental risk factors responsible for individual differences in AU; and (3) to determine the moderating roles of key environmental risk factors on the impact of aggregate molecular, or polygenic, risk for AU during adolescence. Using both biometrical behavioral genetic and molecular genetic methodologies, five key findings were observed: (1) Resilience is strongly associated with a reduction in risk for AUD, and this relationship appears to be the result of overlapping genetic and shared environmental influences; (2) Borderline and antisocial personality disorders are the strongest and most stable personality pathology predictors of the phenotypic and genotypic liability to AU and AUD across time; (3) Genetic influences on the development of AUD from early adulthood to mid-adulthood are dynamic, whereby two sets of genetic risk factors contribute to AUD risk; (4) The specific genetic influences on AU follow an unfolding pattern of growth over time, whereas unique environmental risk factors are consistent with an accumulation of environmental impacts and risks across time; and (5) High peer group deviance and low parental monitoring are associated with increased AU, while early parental monitoring moderates the polygenic risk for AU at age 20. The implications of these results with regard to prevention and intervention efforts are discussed.

Indiana University-Purdue University Indianapolis (IUPUI) / Determining an individual’s genetic susceptibility in complex diseases like Alzheimer’s disease (AD) is challenging as multiple variants each contribute a small portion of the overall risk. Polygenic Risk Scores (PRS) are a mathematical construct or composite that aggregates the small effects of multiple variants into a single score. Potential applications of PRS include risk stratification, biomarker discovery and increased prognostic accuracy. A systematic review demonstrated that methodological refinement of PRS is an active research area, mostly focused on large case-control genome-wide association studies (GWAS). In AD, where there is considerable phenotypic and genetic heterogeneity, we hypothesized that PRS based on endophenotypes, and pathway-relevant genetic information would be particularly informative. In the first study, data from the NIA Alzheimer’s Disease Neuroimaging Initiative (ADNI) was used to develop endophenotype-based PRS based on amyloid (A), tau (T), neurodegeneration (N) and cerebrovascular (V) biomarkers, as well as an overall/combined endophenotype-PRS. Results indicated that combined phenotype-PRS predicted neurodegeneration biomarkers and overall AD risk. By contrast, amyloid and tau-PRSs were strongly linked to the corresponding biomarkers. Finally, extrinsic significance of the PRS approach was demonstrated by application of AD biological pathway-informed PRS to prediction of cognitive changes among older women with breast cancer (BC). Results from PRS analysis of the multicenter Thinking and Living with Cancer (TLC) study indicated that older BC patients with high AD genetic susceptibility within the immune-response and endocytosis pathways have worse cognition following chemotherapy±hormonal therapy rather than hormonal-only therapy. In conclusion, PRSs based on biomarker- or pathway- specific genetic information may provide mechanistic insights beyond disease susceptibility, supporting development of precision medicine with potential application to AD and other age-associated cognitive disorders.

Genome-wide Association Studies (GWAS) is the study used to associate common variants and phenotypes and has uncovered thousands of disease-associated variants. However, there is limited research on the contribution of a rare variant. The UK Biobank (UKB) contains detailed medical records and genetic information for nearly 500,000 individuals and offers a great opportunity for genetic association studies on rare variants. Here we focused on the role of rare protein-coding variants on UKB phenotypes. We selected three diseases for analysis: breast cancer, hypothyroidism and type II diabetes. We defined criteria for qualifying variants and pruned the control group to reduce interference signals from similar phenotypes. We identified the most known biomarkers for those diseases, such as BRCA1 and BRCA2 gene for breast cancer, TG and TSHR gene for hypothyroidism and GCK for type II diabetes. This result supports the model validity and clarifies the contribution of rare variants to diseases. Moreover, we also tried the geneset based collapsing method to aggregate information across genes to strengthen the signal from rare variants and build a diagnosis model that only relies on the genetic information. Our model could achieve great performance with an AUC of more than 20% improvement for type II diabetes and breast cancer and more than 90% accuracy for hypothyroidism.

BACKGROUND: Polygenic risk scores (PRS) have emerged as a promising tool for predicting the risk of developing a variety of illnesses, including psychiatric disorders. PRS are calculated by analyzing the genetic variants across the genome to assess an individual’s risk for developing a disorder. Family history (FHx) of psychiatric disorders has long been recognized as a valuable tool in assessing an individual’s risk in lieu of a genetic blood-based biomarker, like PRS. However, the accuracy of self-reported family history remains limited as a consequence of incomplete or unreliable information collected during a clinical interview. Existing risk factors for developing psychiatric disorders such as FHx tend to be non-specific in their prediction of outcome. Few research studies have evaluated the possibility of using PRS as a complement to FHx across psychosis spectrum disorders. The present study seeks to examine the relationship between the current standard indirect measure of inherited susceptibility being used, FHx, and an individual’s PRS to more directly predict risk of familial susceptibility in those diagnosed with schizophrenia (SZ) by comparing SZ probands based on their FHx of psychotic disorders diagnosis. METHODS: 396 SZ Probands with FHx data were identified. Data on polygenic risk scores for SZ (PRSSCZ) and FHx were obtained from the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium (B-SNIP 1). Genetic susceptibility was identified using PRSSCZ. FHx was established from detailed family interviews. SZ probands with only an affected first-degree relative (n= 42) or only an affected second-degree relative (n= 55) with history of a psychotic disorder diagnosis were included in the analyses. SZ probands without any affected relative (n=179) were used as a comparison group. Demographic information for all participant groups were compared using Chi-square for categorical variables, and ANOVA for continuous variables. ANCOVA was used to identify differences among relative proximity and PRSSCZ while accounting for covariates (age, sex, race). Multiple comparisons were adjusted for using Bonferroni correction. Healthy controls were added as a reference only. The significance level was set at p < 0.05. RESULTS: In SZ probands, there was a significant difference between those with an affected first-degree relative with non-affective psychosis and those without any affected relatives (p< 0.05). No significant difference was observed between those with an affected second-degree relative with non-affective psychosis and those without any affected relatives. Having only an affected first-degree relative with non-affective psychosis carries significantly more risk than having only an affected second-degree relative with non-affective psychosis (p< 0.05). CONCLUSIONS: These findings a) support the validity of taking careful family history of non-affective psychosis diagnosis when evaluating individuals with a psychotic disorder, b) suggest that PRSSCZ may be a useful complement to taking family history, and c) relative proximity is important in risk for SZ. The limitations of this study include lack of direct interviews of affected first- and second-degree relatives, and the lack of complete pedigree information that might allow for calculation of familial load.