Genetic predisposition to psychiatric disorders and risk of COVID-19

AbstractBackgroundPre-pandemic psychiatric disorders have been associated with an increased risk of COVID-19. However, the underlying mechanisms remain unknown, e.g. to what extent genetic predisposition to psychiatric disorders contributes to the observed association.MethodsThe analytic sample consisted of white British participants of UK Biobank registered in England, with available genetic data, and alive on Jan 31, 2020 (i.e., the start of the COVID-19 outbreak in the UK) (n=346,554). We assessed individuals’ genetic predisposition to different psychiatric disorders, including substance misuse, depression, anxiety, and psychotic disorder, using polygenic risk score (PRS). Diagnoses of psychiatric disorders were identified through the UK Biobank hospital inpatient data. We performed a GWAS analysis for each psychiatric disorder in a randomly selected half of the study population who were free of COVID-19 (i.e., the base dataset). For the other half (i.e., the target dataset), PRS was calculated for each psychiatric disorder using the discovered genetic variants from the base dataset. We then examined the association between PRS of each psychiatric disorder and risk of COVID-19, or severe COVID-19 (i.e., hospitalization and death), using logistic regression models. The ascertainment of COVID-19 was through the Public Health England dataset, the UK Biobank hospital inpatient data and death registers, updated until July 26, 2020. For validation, we repeated the PRS analyses based on publicly available GWAS summary statistics.Results155,988 participants (including 1,451 COVID-19 cases), with a mean age of 68.50 years at COVID-19 outbreak, were included for PRS analysis. Higher genetic liability forwards psychiatric disorders was associated with increased risk of both any COVID-19 and severe COVID-19, especially genetic risk for substance misuse and depression. The adjusted odds ratios (ORs) for any COVID-19 were 1.15 (95% confidence interval [CI] 1.02-1.31) and 1.26 (1.11-1.42) among individuals with a high genetic risk (above the upper tertile of PRS) for substance misuse and depression, respectively, compared with individuals with a low genetic risk (below the lower tertile). Largely similar ORs were noted for severe COVID-19 and similar albeit slightly lower estimates using PRSs generated from GWAS summary statistics from independent samples.ConclusionIn the UK Biobank, genetic predisposition to psychiatric disorders was associated with an increased risk of COVID-19, including severe course of the disease. These findings suggest the potential role of genetic factors in the observed phenotypic association between psychiatric disorders and COVID-19, underscoring the need of increased medical surveillance of for this vulnerable population during the pandemic.

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Associations of ophthalmic and systemic conditions with incident dementia in the UK Biobank

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2021-319508 ◽

2021 ◽

pp. bjophthalmol-2021-319508

Author(s):

Xianwen Shang ◽

Zhuoting Zhu ◽

Yu Huang ◽

Xueli Zhang ◽

Wei Wang ◽

...

Keyword(s):

Heart Disease ◽

Age Related Macular Degeneration ◽

Hospital Inpatient ◽

Uk Biobank ◽

Age Related ◽

Incident Dementia ◽

Increased Risk ◽

The Uk ◽

Systemic Condition

AimsTo examine independent and interactive associations of ophthalmic and systemic conditions with incident dementia.MethodsOur analysis included 12 364 adults aged 55–73 years from the UK Biobank cohort. Participants were assessed between 2006 and 2010 at baseline and were followed up until the early of 2021. Incident dementia was ascertained using hospital inpatient, death records and self-reported data.ResultsOver 1 263 513 person-years of follow-up, 2304 cases of incident dementia were documented. The multivariable-adjusted HRs (95% CI) for dementia associated with age-related macular degeneration (AMD), cataract, diabetes-related eye disease (DRED) and glaucoma at baseline were 1.26 (1.05 to 1.52), 1.11 (1.00 to 1.24), 1.61 (1.30 to 2.00) and (1.07 (0.92 to 1.25), respectively. Diabetes, heart disease, stroke and depression at baseline were all associated with an increased risk of dementia. Of the combination of AMD and a systemic condition, AMD-diabetes was associated with the highest risk for incident dementia (HR (95% CI): 2.73 (1.79 to 4.17)). Individuals with cataract and a systemic condition were 1.19–2.29 times more likely to develop dementia compared with those without cataract and systemic conditions. The corresponding number for DRED and a systemic condition was 1.50–3.24. Diabetes, hypertension, heart disease, depression and stroke newly identified during follow-up mediated the association between cataract and incident dementia as well as the association between DRED and incident dementia.ConclusionsAMD, cataract and DRED but not glaucoma are associated with an increased risk of dementia. Individuals with both ophthalmic and systemic conditions are at higher risk of dementia compared with those with an ophthalmic or systemic condition only.

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Pre-pandemic psychiatric disorders and risk of COVID-19: a cohort analysis in the UK Biobank

10.1101/2020.08.07.20169847 ◽

2020 ◽

Cited By ~ 1

Author(s):

Huazhen Yang ◽

Wenwen Chen ◽

Yao Hu ◽

Yilong Chen ◽

Yu Zeng ◽

...

Keyword(s):

Psychiatric Disorders ◽

Cohort Analysis ◽

Uk Biobank ◽

Hospital Data ◽

Logistic Regression Models ◽

Inpatient Hospital ◽

Increased Risk ◽

Somatic Comorbidities ◽

The Uk ◽

Study Participants

Objective To determine the association between pre-pandemic psychiatric disorders and the risk of COVID-19. Design Community-based prospective cohort study. Setting UK Biobank population. Participants 421,048 participants who were recruited in England and alive by January 31st 2020, i.e., the start of COVID-19 outbreak in the UK. 50,815 individuals with psychiatric disorders recorded in the UK Biobank inpatient hospital data before the outbreak were included in the exposed group, while 370,233 participants without such conditions were in the unexposed group. Measurements We obtained information on positive results of COVID-19 test as registered in the Public Health England, COVID-19 related hospitalizations in the UK Biobank inpatient hospital data, and COIVD-19 related deaths from the death registers. We also identified individuals who was hospitalized for infections other than COVID-19 during the follow-up. Logistic regression models were used to estimate odds ratios (ORs) with 95% confidence intervals (CIs), controlling for multiple confounders. Results The mean age at outbreak was 67.8 years and around 43% of the study participants were male. We observed an elevated risk of COVID-19 among individuals with pre-pandemic psychiatric disorder, compared with those without such diagnoses. The fully adjusted ORs were 1.44 (95%CI 1.27 to 1.64), 1.67 (1.42 to 1.98), and 2.03 (1.56 to 2.63) for any COVID-19, inpatient COVID-19, COVID-19 related death, respectively. The excess risk was observed across all levels of somatic comorbidities and subtypes of pre-pandemic psychiatric disorders, while further increased with greater number of pre-pandemic psychiatric disorders. We also observed an association between pre-pandemic psychiatric disorders and increased risk of hospitalization for other infections (1.85 [1.65 to 2.07]). Conclusions Pre-pandemic psychiatric disorders are associated with increased risk of COVID-19, especially severe and fatal COVID-19. The similar association observed for hospitalization for other infections suggests a shared pathway between psychiatric disorders and different infections, including altered immune responses.

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A cross-disorder MR-pheWAS of 5 major psychiatric disorders in UK Biobank

10.1101/634774 ◽

2019 ◽

Author(s):

Beate Leppert ◽

Louise AC Millard ◽

Lucy Riglin ◽

George Davey Smith ◽

Anita Thapar ◽

...

Keyword(s):

Psychiatric Disorders ◽

Computer Games ◽

Genetic Risk ◽

Autism Spectrum ◽

Uk Biobank ◽

First Sexual Intercourse ◽

Hyperactivity Disorder ◽

Socio Demographic Factors ◽

The Uk

ABSTRACTPsychiatric disorders are highly heritable and associated with a wide variety of social adversity and physical health problems. Using genetic liability (rather than phenotypic measures of disease) as a proxy for psychiatric disease risk can be a useful alternative for research questions that would traditionally require large cohort studies with long-term follow up.Here we conducted a hypothesis-free phenome-wide association study in about 300,000 participants from the UK Biobank to examine associations of polygenic risk scores (PRS) for five psychiatric disorders (major depression (MDD), bipolar disorder (BP), schizophrenia (SCZ), attention-deficit/ hyperactivity disorder (ADHD) and autism spectrum disorder (ASD)) with 23,004 outcomes in UK Biobank, using the open-source PHESANT software package.There was evidence after multiple testing (p<2.55×10−06) for associations of PRSs with 226 outcomes, most of them attributed to associations of PRSMDD (n=120) with mental health factors and PRSADHD (n=77) with socio-demographic factors. Among others, we found strong evidence of associations between a 1 standard deviation increase in PRSADHD with 1.1 months younger age at first sexual intercourse [95% confidence interval [CI]: −1.26,−0.94]; PRSASD with 0.01% reduced lower erythrocyte distribution width [95%CI: −0.013,-0.007]; PRSSCZ with 0.98 odds of playing computer games [95%CI:0.976,0.989]; PRSMDD with a 0.11 points higher neuroticism score [95%CI:0.094,0.118] and PRSBP with 1.04 higher odds of having a university degree [95%CI:1.033,1.048].We were able to show that genetic liabilities for five major psychiatric disorders associate with long-term aspects of adult life, including socio-demographic factors, mental and physical health. This is evident even in individuals from the general population who do not necessarily present with a psychiatric disorder diagnosis.AUTHOR SUMMARYPsychiatric disorders are associated with a wide range of adverse health, social and economic problems. Our study investigates the association of genetic risk for five common psychiatric disorders with socio-demographics, lifestyle and health of about 330,000 participants in the UK Biobank using a systematic, hypothesis-free approach. We found that genetic risk for attention deficit/hyperactivity disorder (ADHD) and bipolar disorder were most strongly associated with lifestyle factors, such as time of first sexual intercourse and educational attainment. Genetic risks for autism spectrum disorder and schizophrenia were associated with altered blood cell counts and time playing computer games, respectively. Increased genetic risk for depression was associated with other mental health outcomes such as neuroticism and irritability. In general, our results suggest that genetic risk for psychiatric disorders associates with a range of health and lifestyle traits that were measured in adulthood, in individuals from the general population who do not necessarily present with a psychiatric disorder diagnosis. However, it is important to note that these associations aren’t necessary causal but can themselves be influenced by other factors, like socio-economic factors and selection into the cohort. The findings inform future hypotheses to be tested using causally informative designs.

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Genetic risk scores for major psychiatric disorders and the risk of postpartum psychiatric disorders

Translational Psychiatry ◽

10.1038/s41398-019-0629-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

Anna E. Bauer ◽

Xiaoqin Liu ◽

Enda M. Byrne ◽

Patrick F. Sullivan ◽

Naomi R. Wray ◽

...

Keyword(s):

Psychiatric Disorder ◽

Psychiatric Disorders ◽

Genetic Risk ◽

Case Control ◽

Risk Scores ◽

Psychiatric History ◽

Genetic Risk Scores ◽

Increased Risk ◽

Postpartum Disorders ◽

Postpartum Psychiatric Disorders

Abstract Postpartum psychiatric disorders are heritable, but how genetic liability varies by other significant risk factors is unknown. We aimed to (1) estimate associations of genetic risk scores (GRS) for major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ) with postpartum psychiatric disorders, (2) examine differences by prior psychiatric history, and (3) compare genetic and familial risk of postpartum psychiatric disorders. We conducted a nested case-control study based on Danish population-based registers of all women in the iPSYCH2012 cohort who had given birth before December 31, 2015 (n = 8850). Cases were women with a diagnosed psychiatric disorder or a filled psychotropic prescription within one year after delivery (n = 5829 cases, 3021 controls). Association analyses were conducted between GRS calculated from Psychiatric Genomics Consortium discovery meta-analyses for MD, BD, and SCZ and case-control status of a postpartum psychiatric disorder. Parental psychiatric history was associated with postpartum psychiatric disorders among women with previous psychiatric history (OR, 1.14; 95% CI 1.02–1.28) but not without psychiatric history (OR, 1.08; 95% CI: 0.81–1.43). GRS for MD was associated with an increased risk of postpartum psychiatric disorders in both women with (OR, 1.44; 95% CI: 1.19–1.74) and without (OR, 1.88; 95% CI: 1.26–2.81) personal psychiatric history. SCZ GRS was only minimally associated with postpartum disorders and BD GRS was not. Results suggest GRS of lifetime psychiatric illness can be applied to the postpartum period, which may provide clues about distinct environmental or genetic elements of postpartum psychiatric disorders and ultimately help identify vulnerable groups.

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Abstract 71: Sex and Genetic Predisposition Synergistically Influence Risk of Stroke and Myocardial Infarction in Middle-Aged Persons Without Risk Factors

Stroke ◽

10.1161/str.51.suppl_1.71 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Guido J Falcone ◽

Julian Acosta ◽

Audrey C Leasure ◽

Kevin N Vanent ◽

Rommell B Noche ◽

...

Keyword(s):

Risk Factors ◽

Myocardial Infarction ◽

Genetic Predisposition ◽

Genetic Risk ◽

Vascular Risk Factors ◽

Vascular Risk ◽

Uk Biobank ◽

Middle Aged ◽

High Genetic Risk ◽

The Uk

Background and Hypothesis: Driven by aging-related physiological changes, the incidence of stroke and myocardial infarction rises rapidly in persons aged >40 years. A significant proportion of these acute vascular events (AVE) take place in persons without vascular risk factors. We tested the hypothesis that sex and genetic predisposition synergistically increase the risk of AVE in middle-aged persons without vascular risk factors. Methods: We analyzed data from the UK Biobank, a prospective longitudinal study that enrolled persons aged 40 to 69 years. Our analysis was restricted to middle-aged participants, defined as those aged 40 to 60 years. Prevalent and incident cases of stroke (ischemic and hemorrhagic) and myocardial infarction were included. To quantify the genetic predisposition to sustain an AVE, we constructed a polygenic risk score using 68 independent (R 2 <0.1) genetic variants known to associate (p<5x10 -8 ) with AVE. Participants were classified as having low, intermediate or high genetic risk according to tertiles of the score. We used Cox models for association and interaction testing. Results: Of the 502,536 study participants enrolled in the UK Biobank, 303,295 (60%) did not have any vascular risk factors. During the follow-up period, there were 5,746 AVEs, including 1,954 strokes and 3,792 myocardial infarctions. The cumulative risk of AVE was 0.12% (n=352), 0.46% (n = 1,386) and 1.32% (n = 4,008) at ages 40, 50 and 60 years (test-for-trend p<0.001). The risk of AVE was 3 times greater in men than women (HR 3.30, 95%CI 3.08 - 3.53). Compared to persons with low genetic risk, those with intermediate and high genetic risk had a 22% (HR 1.22, 95%CI 1.13 - 1.32) and 52% (HR 1.52, 95%CI 1.41 - 1.65) increase in risk of AVE, respectively. There was significant synergy (interaction) between sex and genetic predisposition: compared to females with low genetic risk, males with high genetic risk had 4 times (HR 3.91, 95%CI 3.58 - 4.26) the risk of AVE (interaction analysis p<0.001). Conclusion: Genetic information constitutes a promising tool to risk stratify middle-aged persons without vascular risk factors. The synergistic effect of sex and genetic predisposition points to specific subgroups that could benefit from aggressive preventive interventions.

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A Genetically Defined Male Counterpart of Polycystic Ovary Syndrome: Evidence for Ovarian-Independent Pathogenesis

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1574 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A773-A774

Author(s):

Jia Zhu ◽

Laura Brigitte Leen Wittemans ◽

Cecilia Lindgren ◽

Joel N Hirschhorn ◽

Yee-Ming Chan

Keyword(s):

Genetic Risk ◽

Hemoglobin A1c ◽

Polycystic Ovary ◽

Male Counterpart ◽

Uk Biobank ◽

Ovary Syndrome ◽

Increased Risk ◽

Artery Disease ◽

The Uk

Abstract Background: Polycystic ovary syndrome (PCOS) is a heterogeneous condition that affects 6-10% of women of reproductive age. PCOS is often characterized by a triad of ovulatory dysfunction, hyperandrogenism, and cardiometabolic dysfunction. Both ovarian-related and ovarian-independent factors have been implicated in the pathogenesis of PCOS, but it remains to be determined which are the inciting events and which are the secondary consequences. Studies of male relatives of women with PCOS have proposed a male counterpart of PCOS, which suggests that PCOS is not always a primary disorder of female reproduction, but rather can be, at least in part, a condition of cardiometabolic dysregulation and hyperandrogenism, with ovarian dysfunction as a secondary consequence. Methods: To investigate a genetically defined male counterpart of PCOS, we optimized a polygenic risk score (PRS) algorithm for predicting PCOS based on 206,851 unrelated women of European ancestry in the UK Biobank, then used this algorithm to calculate PCOS PRS for 176,360 men in the UK Biobank. We used logistic regression to calculate odds ratios for dichotomous outcomes by comparing men with high and low PRS (testing a variety of percentile cutoffs) and ANCOVA to compare continuous outcomes across deciles of PRS. All analyses were adjusted for age, age2, assessment center, genotyping array, and the first 10 principal genetic components to account for ancestry. Results: Men who carried a high PCOS PRS (top 20%) had a 17% increased risk of obesity defined as BMI ≥30 kg/m2 (OR 1.17, 95% confidence interval [CI] 1.14-1.20, p=1.3x10-30), 15% increased risk of type 2 diabetes mellitus (OR 1.15, 95% CI 1.09-1.20, p=5.3x10-8), 5% increased risk of coronary artery disease (OR 1.05, 95% CI 1.01-1.09, p=0.03), and 5% increased risk for androgenic alopecia (OR 1.05, 95% CI 1.01-1.08, p=0.01). BMI, hemoglobin A1c, triglycerides, and the free androgen index all increased across deciles of the PRS, while HDL and SHBG decreased across PRS deciles (p all <0.001). The relationship between the PCOS PRS and coronary artery disease, HDL, and triglycerides appeared to be mediated by BMI. In contrast, the associations between the PCOS PRS and type 2 diabetes mellitus and hemoglobin A1c remained significant after adjusting for BMI, suggesting independent mechanisms of pathogenesis. Conclusions: By demonstrating associations between PCOS genetic risk factors and cardiometabolic dysfunction and androgenic conditions in men, we have shown that these genetic risk factors can act independently of ovarian function. Thus, at least in some cases, the reproductive dysfunction of PCOS in women may arise secondarily from disruption of biological pathways common to both men and women. Future dissection of these biological pathways will further inform efforts to identify pathological mechanisms underlying PCOS.

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Associations between psychiatric disorders, COVID-19 testing probability and COVID-19 testing results: findings from a population-based study

BJPsych Open ◽

10.1192/bjo.2020.75 ◽

2020 ◽

Vol 6 (5) ◽

Cited By ~ 3

Author(s):

Dennis van der Meer ◽

Justo Pinzón-Espinosa ◽

Bochao D. Lin ◽

Joeri K. Tijdink ◽

Christiaan H. Vinkers ◽

...

Keyword(s):

Psychiatric Disorder ◽

Psychiatric Disorders ◽

Population Based ◽

Sensitivity Analyses ◽

Test Results ◽

Uk Biobank ◽

Full Cohort ◽

Population Based Study ◽

Association Analyses ◽

Increased Risk

Background Many psychiatrists are worried their patients, at increased risk for COVID-19 complications, are precluded from receiving appropriate testing. There is a lack of epidemiological data on the associations between psychiatric disorders and COVID-19 testing rates and testing outcomes. Aims To compare COVID-19 testing probability and results among individuals with psychiatric disorders with those without such diagnoses, and to examine the associations between testing probability and results and psychiatric diagnoses. Method This is a population-based study to perform association analyses of psychiatric disorder diagnoses with COVID-19 testing probability and such test results, by using two-sided Fisher exact tests and logistic regression. The population were UK Biobank participants who had undergone COVID-19 testing. The main outcomes were COVID-19 testing probability and COVID-19 test results. Results Individuals with psychiatric disorders were overrepresented among the 1474 UK Biobank participants with test data: 23% of the COVID-19 test sample had a psychiatric diagnosis compared with 10% in the full cohort (P < 0.0001). This overrepresentation persisted for each of the specific psychiatric disorders tested. Furthermore, individuals with a psychiatric disorder (P = 0.01), particularly substance use disorder (P < 0.005), had negative test results significantly more often than individuals without psychiatric disorders. Sensitivity analyses confirmed our results. Conclusions In contrast with our hypotheses, UK Biobank participants with psychiatric disorders have been tested for COVID-19 more frequently than individuals without a psychiatric history. Among those tested, test outcomes were more frequently negative for registry participants with psychiatric disorders than in others, countering arguments that people with psychiatric disorders are particularly prone to contract the virus.

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Genetic risk factors for death with SARS-CoV-2 from the UK Biobank

10.1101/2020.07.01.20144592 ◽

2020 ◽

Cited By ~ 1

Author(s):

Chang Lu ◽

Rihab Gam ◽

Arun Prasad Pandurangan ◽

Julian Gough

Keyword(s):

Risk Factors ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Uk Biobank ◽

Factors Affecting ◽

Risk Of Death ◽

Global Pandemic ◽

Risk Variants ◽

Increased Risk ◽

The Uk

AbstractWe present here genetic risk factors for survivability from infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for coronavirus disease 19 (COVID-19). At the time of writing it is too early to determine comprehensively and without doubt all risk factors, but there is an urgency due to the global pandemic crisis that merits this early analysis. We have nonetheless discovered 5 novel risk variants in 4 genes, discovered by examining 193 deaths from 1,412 confirmed infections in a group of 5,871 UK Biobank participants tested for the virus. We also examine the distribution of these genetic variants across broad ethnic groups and compare it to data from the UK Office of National Statistics for increased risk of death from SARS-CoV-2. We confidently identify the gene ERAP2 with a high-risk variant, as well as three other genes of potential interest. Although mostly rare, a common theme of genetic risk factors affecting survival might be the inability to launch or modulate an effective immune and stress response to infection from the SARS-CoV-2 virus.

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COVID-19 and mortality risk in patients with psychiatric disorders

10.1101/2021.04.08.21255046 ◽

2021 ◽

Author(s):

George Kirov ◽

Emily Baker

Keyword(s):

Mental Health ◽

Bipolar Disorder ◽

Life Expectancy ◽

Psychiatric Disorders ◽

Mortality Risk ◽

Mental Health Problems ◽

Cardiovascular Disorders ◽

Uk Biobank ◽

Increased Risk ◽

The Uk

COVID-19 has already caused the deaths of over 2.5 million people worldwide. Patients with certain medical conditions and severe psychiatric disorders are at increased risk of dying from it. However, such people have a reduced life expectancy anyway, raising the question whether COVID-19 incurs a specific risk for such patients for dying, over and above the risk of dying from other causes. We analysed the UK Biobank data of half a million middle-aged participants from the UK. From the start of 2020 up to 24th January 2021, 894 participants had died from COVID-19 and another 4,562 had died from other causes. We demonstrate that the risk of dying from COVID-19 among patients with mental health problems, especially those with dementia, schizophrenia, or bipolar disorder, is increased compared to the risk of dying from other causes. This increase among patients with severe psychiatric disorders cannot be explained solely by the higher rate of diabetes or cardiovascular disorders.

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The Association of Age at Diagnosis of Hypertension With Brain Structure and Incident Dementia in the UK Biobank

Hypertension ◽

10.1161/hypertensionaha.121.17608 ◽

2021 ◽

Author(s):

Xianwen Shang ◽

Edward Hill ◽

Zhuoting Zhu ◽

Jiahao Liu ◽

B. Zongyuan Ge ◽

...

Keyword(s):

Gray Matter ◽

Brain Volume ◽

Multivariable Analysis ◽

Brain Magnetic Resonance Imaging ◽

Hospital Inpatient ◽

Uk Biobank ◽

Brain Volumes ◽

Increased Risk ◽

The Uk ◽

Diagnosis Of Hypertension

Little is known about whether the association of hypertension with brain volume and dementia is modified by an individual’s age at their diagnosis of hypertension. Our analysis was based on the UK Biobank with baseline data collected between 2006 and 2010. Brain magnetic resonance imaging was used to measure brain volumes between 2014 and 2019. Dementia was ascertained using hospital inpatient, mortality, and self-reported data until 2021. We randomly selected a control participant for each hypertensive participant stratified by hypertension diagnosis age using propensity score. The cohort comprised 11 399 individuals with hypertension and 11 399 controls for the brain volume analysis and 124 053 individuals with hypertension and 124 053 controls for the dementia analysis. Individuals with hypertension diagnosed at ages <35 (β (95% CI, −10.83 [−19.27 to −2.39] mL), 35 to 44 (−6.82 [−12.18 to −1.46] mL), and 45 to 54 years (−3.77 [−6.91 to −0.64] mL) had smaller total brain volume compared with the corresponding controls in the multivariable analysis. Similarly, hypertension diagnosed in early- and mid-life was independently associated with smaller volumes of gray matter, peripheral cortical gray matter, and white matter. Over a median follow-up of 11.9 years, 4626 cases of incident all-cause dementia were documented. Individuals with hypertension diagnosed at 35 to 44 years of age only (hazard ratio [95% CI]: 1.61 [1.31–1.99]) had a higher risk of all-cause dementia compared with the corresponding controls after adjustment for covariates. Hypertension diagnosed in young adulthood or mid-life, but not late life is associated with smaller brain volumes and an increased risk of dementia.

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