Trans-ethnic genomic informed risk assessment for Alzheimer's disease: An International Hundred K+ Cohorts Consortium study.

BACKGROUND: As a collaboration model between the International HundredK+ Cohorts Consortium (IHCC) and the Davos Alzheimer's Collaborative (DAC), our aim was to develop a trans-ethnic genomic informed risk assessment (GIRA) algorithm for Alzheimer's disease (AD). METHODS: The GIRA model was created to include polygenic risk score calculated from the AD genome-wide association study loci, the apolipoprotein E haplotypes, and non-genetic covariates including age, sex, and the first three principal components of population substructure. RESULTS: We validated the performance of the GIRA model in different populations. The proteomic study in the participant sites identified proteins related to female infertility and autoimmune thyroiditis and associated with the risk scores of AD. CONCLUSIONS: As the initial effort by the IHCC to leverage existing large-scale datasets in a collaborative setting with DAC, we developed a trans-ethnic GIRA for AD with the potential of identifying individuals at high risk of developing AD for future clinical applications.

Polygenic risk score prediction of multiple sclerosis in individuals of South Asian ancestry.

Polygenic risk scores aggregate an individual's burden of risk alleles to estimate the overall genetic risk for a specific trait or disease. Polygenic risk scores derived from genome-wide association studies of European populations perform poorly for other ancestral groups. Given the potential for future clinical utility, underperformance of polygenic risk scores in South Asian populations has the potential to reinforce health inequalities. To determine whether European-derived polygenic risk scores underperform at multiple sclerosis prediction in a South Asian-ancestry population compared with a European-ancestry cohort, we used data from two longitudinal genetic cohort studies: Genes & Health (2015-present), a study of ∼50 000 British-Bangladeshi and British-Pakistani individuals, and UK Biobank (2006-present), which is comprised of ∼500 000 predominantly White British individuals. We compared individuals with and without multiple sclerosis in both studies (Genes & Health: N Cases = 42, N Control = 40 490; UK Biobank: N Cases = 2091, N Control = 374 866). Polygenic risk scores were calculated using clumping and thresholding with risk allele effect sizes obtained from the largest multiple sclerosis genome-wide association study to date. Scores were calculated with and without the major histocompatibility complex region, the most influential locus in determining multiple sclerosis risk. Polygenic risk score prediction was evaluated using Nagelkerke's pseudo-R 2 metric adjusted for case ascertainment, age, sex and the first four genetic principal components. We found that, as expected, European-derived polygenic risk scores perform poorly in the Genes & Health cohort, explaining 1.1% (including the major histocompatibility complex) and 1.5% (excluding the major histocompatibility complex) of disease risk. In contrast, multiple sclerosis polygenic risk scores explained 4.8% (including the major histocompatibility complex) and 2.8% (excluding the major histocompatibility complex) of disease risk in European-ancestry UK Biobank participants. These findings suggest that polygenic risk score prediction of multiple sclerosis based on European genome-wide association study results is less accurate in a South Asian population. Genetic studies of ancestrally diverse populations are required to ensure that polygenic risk scores can be useful across ancestries.

Assessment of Risk Factors and Early Presentations of Parkinson Disease in Primary Care in a Diverse UK Population.

IMPORTANCE: Early features of Parkinson disease (PD) have been described through population-based studies that overrepresent White, affluent groups and may not be generalizable. OBJECTIVE: To investigate the association between risk factors and prediagnostic presentations of PD in an ethnically diverse UK population with high socioeconomic deprivation but universal access to health care. DESIGN, SETTING, AND PARTICIPANTS: A nested case-control study was conducted using electronic health care records on 1 016 277 individuals from primary care practices in East London to extract clinical information recorded between 1990 and February 6, 2018. The data were analyzed between September 3, 2020, and September 3, 2021. Individuals with a diagnosis of PD were compared with controls without PD or other major neurological conditions. MAIN OUTCOMES AND MEASURES: A matched analysis (10 controls matched for each patient with PD according to age and sex) and an unmatched analysis (adjusted for age and sex) were undertaken using multivariable logistic regression to determine associations between risk factors and prediagnostic presentations to primary care with subsequent diagnosis of PD. Three time periods (<2, 2-<5, and 5-10 years before diagnosis) were analyzed separately and together. RESULTS: Of 1 016 277 individuals included in the data set, 5699 were excluded and 1055 patients with PD and 1 009 523 controls were included in the analysis. Patients with PD were older than controls (mean [SD], 72.9 [11.3] vs 40.3 [15.2] years), and more were male (632 [59.9%] vs 516 862 [51.2%]). In the matched analysis (1055 individuals with PD and 10 550 controls), associations were found for tremor (odds ratio [OR], 145.96; 95% CI, 90.55-235.28) and memory symptoms (OR, 8.60; 95% CI, 5.91-12.49) less than 2 years before the PD diagnosis. The associations were also found up to 10 years before PD diagnosis for tremor and 5 years for memory symptoms. Among midlife risk factors, hypertension (OR, 1.36; 95% CI, 1.19-1.55) and type 2 diabetes (OR, 1.39; 95% CI, 1.19-1.62) were associated with subsequent diagnosis of PD. Associations with early nonmotor features, including hypotension (OR, 6.84; 95% CI, 3.38-13.85), constipation (OR, 3.29; 95% CI, 2.32-4.66), and depression (OR, 4.69; 95% CI, 2.88-7.63), were also noted. Associations were found for epilepsy (OR, 2.5; 95% CI, 1.63-3.83) and hearing loss (OR, 1.66; 95% CI, 1.06-2.58), which have not previously been well reported. These findings were replicated using data from the UK Biobank. No association with future PD diagnosis was found for ethnicity or deprivation index level. CONCLUSIONS AND RELEVANCE: This study provides data suggesting that a range of comorbidities and symptoms are encountered in primary care settings before PD diagnosis in an ethnically diverse and deprived population. Novel temporal associations were observed for epilepsy and hearing loss with subsequent development of PD. The prominence of memory symptoms suggests an excess of cognitive dysfunction in early PD in this population or difficulty in correctly ascertaining symptoms in traditionally underrepresented groups.

Ethnic and Socioeconomic Associations with Multiple Sclerosis Risk.

OBJECTIVE: Epidemiological research in multiple sclerosis (MS) has mainly been performed in socioeconomically and ethnically limited populations; influences on MS risk have not been studied in prospectively collected non-White populations. We set out to study the influence of previously described MS risk factors in an ethnically diverse population. METHODS: A nested case-control study was created using primary care records of >1 million individuals, >50% of whom identify as Black, Asian, and Minority Ethnic (BAME). MS cases were compared to an age- and sex-matched control cohort (1:4), and to a large unmatched cohort. Odds ratios (ORs) of disease were determined according to exposure of interest, and a multivariate model including all exposures was created. Potential pairwise interactions were considered where both indicated a significant effect. RESULTS: A total of 1,344 confirmed MS cases were included. MS OR in blacks aged <40 years was 1.15 (95% confidence interval [CI] = 0.81-1.62) compared to whites. MS odds in BAME current (OR = 1.71, 95% CI = 1.24-2.31) and ex-smokers (OR = 2.83, 95% CI = 2.14-3.72) were considerably higher than in Whites (OR = 1.09, 95% CI = 0.88-1.34; OR = 1.44, 95% CI = 1.19-1.74, respectively). Prior infectious mononucleosis was associated with increased odds of MS in Blacks (OR = 4.94, 95% CI = 1.23-17.89). An increase in MS odds was seen in the least-deprived quintile (OR = 2.46, 95% CI = 1.40-4.24), but no effect across deprived quintiles was seen. INTERPRETATION: This cohort provides novel data on factors potentially driving MS susceptibility in a diverse population, one-third of whom live in poverty. Environmental exposures have differential risk across ethnicity. ANN NEUROL 2020;87:599-608.

Assessment of mouse cognitive and anxiety-like behaviors and hippocampal inflammation following a repeated and intermittent paradoxical sleep deprivation procedure.

It has been reported that more than one fourth of the world's population suffers from sleep problems. However, there is not a stable and reliable animal model to mimic the persistent and periodic features of sleep disorders, and correspondingly, the feasibility and effectiveness of repeated behavioral tests remains to be determined. In the present study, we repetitively, and intermittently, treated mice with 3days and 7days of paradoxical sleep deprivation (SD), using the modified multiple small-platforms-over-water method for 3 months. The behavioral results suggested that repeated open field and Y-maze tests are able to successfully detect anxiety-like behaviors and working memory dysfunction of the model mice. The Morris water maze test is not suitable for evaluating spatial learning ability following SD because the long-term utilization of the flower-pot method increases the familiarity of mice with the water environment. Moreover, neuroinflammation, microglial activation and neuronal apoptosis were observed in the hippocampus of model mice even recovery for 3 weeks later. This animal model and corresponding behavioral evaluation method will help to explore the pathogenesis and therapeutic strategies of chronic sleep disorders.