Methylomic and transcriptomic predictors of one-month exposure to cortisol in healthy individuals.

Allostatic load (AL) refers to the cumulative "wear and tear" on an organism throughout its lifetime. One of the primary contributing factors to AL is prolonged exposure to stress or its primary catabolic agent cortisol. Chronic exposure to stress or cortisol is associated with numerous diseases, including cardiovascular disease, metabolic disorders, and psychiatric disorders. Therefore, a molecular marker capable of integrating a past history of cortisol exposure would be of great utility for assessing disease risk. To this end, we recruited 87 healthy males and females of European ancestry between 18 and 60 years old, extracted genomic DNA and RNA from leukocytes, and implemented a gene-centric DNA enrichment method coupled with bisulfite sequencing and RNA-Seq of total RNA for the determination of genome-wide methylation and gene transcription, respectively. Sequencing data were analyzed against awakening and bedtime cortisol data to identify differentially methylated regions (DMRs) and CpGs (DMCs) and differentially expressed genes (DEGs). Six candidate DMCs (punadjusted < 0.005) and nine DEGs (punadjusted < 0.0005) were used to construct a prediction model that could capture past 30+ days of both bedtime and awakening cortisol levels. Utilizing a cross-validation approach, we obtained a regression coefficient of R2 = 0.308 for predicting continuous awakening cortisol and an area under the curve (AUC) = 0.753 for dichotomous (high vs. low tertile) awakening cortisol, and R2 = 0.224 and AUC = 0.723 for continuous and dichotomous bedtime cortisol levels, respectively. To our knowledge, the current study represents the first attempt to identify genome-wide predictors of cortisol exposure that utilizes both methylation and transcription targets. The utility of our approach needs to be replicated in an independent cohort of samples for which similar cortisol metrics are available.

Polygenic and environmental influences on the course of African Americans' alcohol use from early adolescence through young adulthood.

The study examined (a) whether alcohol use subgroups could be identified among African Americans assessed from adolescence through early adulthood, and (b) whether subgroup membership was associated with the interaction between internalizing symptoms and antisocial behavior polygenic risk scores (PRSs) and environmental characteristics (i.e., parental monitoring, community disadvantage). Participants (N = 436) were initially recruited for an elementary school-based prevention trial in a Mid-Atlantic city. Youths reported on the frequency of their past year alcohol use from ages 14-26. DNA was obtained from participants at age 21. Internalizing symptoms and antisocial behavior PRSs were created based on a genome-wide association study (GWAS) conducted by Benke et al. (2014) and Tielbeek et al. (2017), respectively. Parental monitoring and community disadvantage were assessed at age 12. Four classes of past year alcohol use were identified: (a) early-onset, increasing; (b) late-onset, moderate use; (c) low steady; and (d) early-onset, decreasing. In high community disadvantaged settings, participants with a higher internalizing symptoms PRS were more likely to be in the early-onset, decreasing class than the low steady class. When exposed to elevated community disadvantage, participants with a higher antisocial behavior PRS were more likely to be in the early-onset, increasing class than the early-onset, decreasing and late-onset, moderate use classes.

Differentially methylated regions in bipolar disorder and suicide.

The addition of a methyl group to, typically, a cytosine-guanine dinucleotide (CpG) creates distinct DNA methylation patterns across the genome that can regulate gene expression. Aberrant DNA methylation of CpG sites has been associated with many psychiatric disorders including bipolar disorder (BD) and suicide. Using the SureSelectXT system, Methyl-Seq, we investigated the DNA methylation status of CpG sites throughout the genome in 50 BD individuals (23 subjects who died by suicide and 27 subjects who died from other causes) and 31 nonpsychiatric controls. We identified differentially methylated regions (DMRs) from three analyses: (a) BD subjects compared to nonpsychiatric controls (BD-NC), (b) BD subjects who died by suicide compared to nonpsychiatric controls (BDS-NC), and (c) BDS subjects compared to BD subjects who died from other causes (BDS-BDNS). One DMR from the BDS-NC analysis, located in ARHGEF38, was significantly hypomethylated (23.4%) in BDS subjects. This finding remained significant after multiple testing (PBootstrapped = 9.0 × 10-3 ), was validated using pyrosequencing, and was more significant in males. A secondary analysis utilized Ingenuity Pathway Analysis to identify enrichment in nominally significant DMRs. This identified an association with several pathways including axonal guidance signaling, calcium signaling, ß-adrenergic signaling, and opioid signaling. Our comprehensive study provides further support that DNA methylation alterations influence the risk for BD and suicide. However, further investigation is required to confirm these associations and identify their functional consequences.

Exposures and conditions prior to age 16 are associated with dementia status among adults in the United States Health and Retirement Study.

Background: Dementia susceptibility likely begins years before symptoms. Early life has not been comprehensively tested for dementia associations. Method: In the US Health and Retirement Study (normal baseline cognition; n=16,509; 2008-2018 waves), 31 exposures before age 16 were retrospectively assessed with ten-year incident cognitive status (dementia, impaired, normal). Using parallel logistic models, each exposure was tested with incident cognition, adjusting for sex, baseline age, follow-up, race/ethnicity, personal/parental education. Result: 14.5% had incident impairment and 5.3% had dementia. Depression was associated with 1.71 (95%CI:1.28,2.26) times higher odds of incident impairment, relative to normal cognition. Headaches/migraines were associated with 1.63 (95%CI:1.18,2.22) times higher odds of incident impairment. Learning problems were associated with 1.75 (95%CI:1.05,2.79) times higher odds of incident impairment. Childhood self-rated health of fair (1.86, 95%CI:1.27,2.64) and poor (3.39, 95%CI:1.91,5.82) were associated with higher incident dementia odds, relative to excellent. Conclusion: Early life factors may be important for impairment or dementia, extending the relevant risk window.

Prenatal vitamin intake in first month of pregnancy and DNA methylation in cord blood and placenta in two prospective cohorts.

BACKGROUND: Prenatal vitamin use is recommended before and during pregnancies for normal fetal development. Prenatal vitamins do not have a standard formulation, but many contain calcium, folic acid, iodine, iron, omega-3 fatty acids, zinc, and vitamins A, B6, B12, and D, and usually they contain higher concentrations of folic acid and iron than regular multivitamins in the US Nutrient levels can impact epigenetic factors such as DNA methylation, but relationships between maternal prenatal vitamin use and DNA methylation have been relatively understudied. We examined use of prenatal vitamins in the first month of pregnancy in relation to cord blood and placenta DNA methylation in two prospective pregnancy cohorts: the Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk Learning Early Signs (MARBLES) studies. RESULTS: In placenta, prenatal vitamin intake was marginally associated with -0.52% (95% CI -1.04, 0.01) lower mean array-wide DNA methylation in EARLI, and associated with -0.60% (-1.08, -0.13) lower mean array-wide DNA methylation in MARBLES. There was little consistency in the associations between prenatal vitamin intake and single DNA methylation site effect estimates across cohorts and tissues, with only a few overlapping sites with correlated effect estimates. However, the single DNA methylation sites with p-value < 0.01 (EARLI cord nCpGs = 4068, EARLI placenta nCpGs = 3647, MARBLES cord nCpGs = 4068, MARBLES placenta nCpGs = 9563) were consistently enriched in neuronal developmental pathways. CONCLUSIONS: Together, our findings suggest that prenatal vitamin intake in the first month of pregnancy may be related to lower placental global DNA methylation and related to DNA methylation in brain-related pathways in both placenta and cord blood.

Placental methylome reveals a 22q13.33 brain regulatory gene locus associated with autism.

BACKGROUND: Autism spectrum disorder (ASD) involves complex genetics interacting with the perinatal environment, complicating the discovery of common genetic risk. The epigenetic layer of DNA methylation shows dynamic developmental changes and molecular memory of in utero experiences, particularly in placenta, a fetal tissue discarded at birth. However, current array-based methods to identify novel ASD risk genes lack coverage of the most structurally and epigenetically variable regions of the human genome. RESULTS: We use whole genome bisulfite sequencing in placenta samples from prospective ASD studies to discover a previously uncharacterized ASD risk gene, LOC105373085, renamed NHIP. Out of 134 differentially methylated regions associated with ASD in placental samples, a cluster at 22q13.33 corresponds to a 118-kb hypomethylated block that replicates in two additional cohorts. Within this locus, NHIP is functionally characterized as a nuclear peptide-encoding transcript with high expression in brain, and increased expression following neuronal differentiation or hypoxia, but decreased expression in ASD placenta and brain. NHIP overexpression increases cellular proliferation and alters expression of genes regulating synapses and neurogenesis, overlapping significantly with known ASD risk genes and NHIP-associated genes in ASD brain. A common structural variant disrupting the proximity of NHIP to a fetal brain enhancer is associated with NHIP expression and methylation levels and ASD risk, demonstrating a common genetic influence. CONCLUSIONS: Together, these results identify and initially characterize a novel environmentally responsive ASD risk gene relevant to brain development in a hitherto under-characterized region of the human genome.

A learning algorithm for predicting mental health symptoms and substance use.

Learning health systems use data to generate knowledge that informs clinical care, but few studies have evaluated how to leverage patient-reported mental health symptoms and substance use data to make patient-specific predictions. We developed a general Bayesian prediction algorithm that uses self-reported psychiatric symptoms and substance use within a population to predict future symptoms and substance use for individuals in that population. We validated our approach in 2444 participants from two clinical cohorts - the National Network of Depression Centers and the Johns Hopkins HIV Clinical Cohort - by predicting symptoms of depression, anxiety, and mania as well as alcohol, heroin, and cocaine use and comparing our predictions to observed symptoms and substance use. When we dichotomized mental health symptoms as moderate-severe vs. none-mild, individual predictions yielded areas under the ROC curve (AUCs) of 0.84 [95% confidence interval 0.80-0.88] and 0.85 [0.82-0.88] for symptoms of depression in the two cohorts, AUCs of 0.84 [0.79-0.88] and 0.85 [0.82-0.88] for symptoms of anxiety, and an AUC of 0.77 [0.72-0.82] for manic symptoms. Predictions of substance use yielded an AUC of 0.92 [0.88-0.97] for heroin use, 0.90 [0.82-0.97] for cocaine use, and 0.90 [0.88-092] for alcohol misuse. This rigorous, mathematically grounded approach could provide patient-specific predictions at the point of care. It can be applied to other psychiatric symptoms and substance use indicators, and is customizable to specific health systems. Such approaches can realize the potential of a learning health system to transform ever-increasing quantities of data into tangible guidance for patient care.

Cumulative Genetic Risk and APOE ε4 Are Independently Associated With Dementia Status in a Multiethnic, Population-Based Cohort.

OBJECTIVE: Alzheimer disease (AD) is a common and costly neurodegenerative disorder. A large proportion of AD risk is heritable, and many genetic risk factors have been identified. The objective of this study was to test the hypothesis that cumulative genetic risk of known AD markers contributed to odds of dementia in a population-based sample. METHODS: In the US population-based Health and Retirement Study (waves 1995-2014), we evaluated the role of cumulative genetic risk of AD, with and without the APOE ε4 alleles, on dementia status (dementia, cognitive impairment without dementia, borderline cognitive impairment without dementia, and cognitively normal). We used logistic regression, accounting for demographic covariates and genetic principal components, and analyses were stratified by European and African genetic ancestry. RESULTS: In the European ancestry sample (n = 8,399), both AD polygenic score excluding the APOE genetic region (odds ratio [OR] = 1.10; 95% confidence interval [CI]: 1.00-1.20) and the presence of any APOE ε4 alleles (OR = 2.42; 95% CI: 1.99-2.95) were associated with the odds of dementia relative to normal cognition in a mutually adjusted model. In the African ancestry sample (n = 1,605), the presence of any APOE ε4 alleles was associated with 1.77 (95% CI: 1.20-2.61) times higher odds of dementia, whereas the AD polygenic score excluding the APOE genetic region was not significantly associated with the odds of dementia relative to normal cognition 1.06 (95% CI: 0.97-1.30). CONCLUSIONS: Cumulative genetic risk of AD and APOE ε4 are both independent predictors of dementia in European ancestry. This study provides important insight into the polygenic nature of dementia and demonstrates the utility of polygenic scores in dementia research.

Genome-wide Association Study of Change in Fasting Glucose over time in 13,807 non-diabetic European Ancestry Individuals.

Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.

Cord blood buffy coat DNA methylation is comparable to whole cord blood methylation.

Cord blood DNA methylation is associated with numerous health outcomes and environmental exposures. Whole cord blood DNA reflects all nucleated blood cell types, while centrifuging whole blood separates red blood cells, generating a white blood cell buffy coat. Both sample types are used in DNA methylation studies. Cell types have unique methylation patterns and processing can impact cell distributions, which may influence comparability. We evaluated differences in cell composition and DNA methylation between cord blood buffy coat and whole cord blood samples. Cord blood DNA methylation was measured with the Infinium EPIC BeadChip (Illumina) in eight individuals, each contributing buffy coat and whole blood samples. We analyzed principal components (PC) of methylation, performed hierarchical clustering, and computed correlations of mean-centered methylation between pairs. We conducted moderated t-tests on single sites and estimated cell composition. DNA methylation PCs were associated with individual (PPC1 = 1.4 × 10-9; PPC2 = 2.9 × 10-5; PPC3 = 3.8 × 10-5; PPC4 = 4.2 × 10-6; PPC5 = 9.9 × 10-13, PPC6 = 1.3 × 10-11) and not with sample type (PPC1-6>0.7). Samples hierarchically clustered by individual. Pearson correlations of mean-centered methylation between paired samples ranged from r = 0.66 to r = 0.87. No individual site significantly differed between buffy coat and whole cord blood when adjusting for multiple comparisons (five sites had unadjusted P<10-5). Estimated cell type proportions did not differ by sample type (P = 0.46), and estimated proportions were highly correlated between paired samples (r = 0.99). Differences in methylation and cell composition between buffy coat and whole cord blood are much lower than inter-individual variation, demonstrating that both sample preparation types can be analytically combined and compared.

Promoter polymorphisms in the plasma glutathione peroxidase (GPx-3) gene: a novel risk factor for arterial ischemic stroke among young adults and children.

BACKGROUND AND PURPOSE: Plasma glutathione peroxidase (GPx-3)-deficiency increases extracellular oxidant stress, decreases bioavailable nitric oxide, and promotes platelet activation. The aim of this study is to identify polymorphisms in the GPx-3 gene, examine their relationship to arterial ischemic stroke (AIS) in a large series of children and young adults, and determine their functional molecular consequences. METHODS: We studied the GPx-3 gene promoter from 123 young adults with idiopathic AIS and 123 age- and gender-matched controls by single-stranded conformational polymorphism and sequencing analysis. A second, independent population with childhood stroke was used for a replication study. We identified 8 novel, strongly linked polymorphisms in the GPx-3 gene promoter that formed 2 main haplotypes (H1 and H2). The transcriptional activity of the 2 most prevalent haplotypes was studied with luciferase reporter gene constructs. RESULTS: The H2 haplotype was over-represented in both patient populations and associated with an independent increase in the risk of AIS in young adults (odds ratio=2.07, 95% CI=1.03 to 4.47; P=0.034) and children (odds ratio=2.13, 95% CI=1.23 to 4.90; P=0.027). In adults simultaneously exposed to vascular risk factors, the risk of AIS approximately doubled (odds ratio=5.18, 95% CI=1.82 to 15.03; P<0.001). Transcriptional activity of the H2 haplotype was lower than that of the H1 haplotype, especially after upregulation by hypoxia (normalized relative luminescence: 3.54+/-0.32 versus 2.47+/-0.26; P=0.0083). CONCLUSIONS: These findings indicate that a novel GPx-3 promoter haplotype is an independent risk factor for AIS in children and young adults. This haplotype reduces the gene's transcriptional activity, thereby compromising gene expression and plasma antioxidant and antithrombotic activities.

Use of susceptibility scoring in conjunction with the genotypic transmission disequilibrium test.

We explored the utility of selecting a genetically predisposed subgroup to increase the finding of a genetic signal in the Genetic Analysis Workshop 14 Collaborative Study on the Genetics of Alcoholism dataset. A subgroup of affected probands with low environmental risk exposures was defined using a susceptibility score calculated from an environmental risk model. Thirty-nine probands with highly positive scores were selected, along with their parents, for use in a genotypic transmission disequilibrium test (TDT) test. We compared the results of the genotypic TDT in this subgroup to the TDT results using all probands and their parents. For some markers, the susceptibility scoring approach resulted in smaller p-values, while for other markers, evidence for a genetic signal weakened. Further explorations into genetic and environmental population characteristics that benefit from this approach are warranted.

Paraoxonase 192 Gln-->Arg polymorphism: an independent risk factor for nonfatal arterial ischemic stroke among young adults.

BACKGROUND AND PURPOSE: The etiology of arterial ischemic stroke (AIS) in the young remains unknown in one third of patients. Serum paraoxonase (PON1) is an HDL-associated esterase that hydrolyzes products of lipid peroxidation and prevents the oxidation of LDL. Two common polymorphisms in the PON1 gene, the 192 Gln (Q) --> Arg (R) and 55 Leu (L) --> Met (M) substitutions, determine interindividual variation in PON1 activity. The association of these polymorphisms with the risk of AIS remains controversial. METHODS: We analyzed 118 patients (64 women) with a first nonfatal AIS occurring <45 years of age and 118 1:1 age (+/-2 years)- and sex-matched controls. The PON1 polymorphisms were determined by polymerase chain reaction amplification and restriction digestion. RESULTS: The prevalence of the PON1 192RR genotype (P=0.006) and the frequency of the R allele (P=0.010) were significantly increased among young AIS patients compared with controls. After adjustment for conventional vascular and prothrombotic risk factors, the 192RR genotype remained independently associated with a 4-fold increase in the risk of AIS (odds ratio=4.1; 95% CI, 1.14 to 14.73). Subanalyses stratified by the presence of vascular risk factors and ethnicity did not significantly modify the effect of the PON1 192 polymorphism on AIS risk. No significant differences were found between patients and controls regarding the PON1 55 polymorphism. CONCLUSIONS: These findings suggest that the PON 192RR genotype is independently associated with an increased risk of nonfatal AIS among young adults. Further studies are necessary to understand better the mechanistic implications of these observations in the development of AIS in the young.

The combined effect of paraoxonase promoter and coding region polymorphisms on the risk of arterial ischemic stroke among young adults.

BACKGROUND: Serum paraoxonase (PON1) is a high-density lipoprotein-associated esterase with antioxidant and antiatherogenic properties that has recently been implicated in the pathogenesis of cardiovascular disease. Interindividual variability in PON1 levels is determined by the Q192R and L55M coding region polymorphisms and by 2 recently described polymorphisms in the promoter of the PON1 gene, C(-107)T and G(-824)A. OBJECTIVE: To determine the association of the PON1 promoter polymorphisms with arterial ischemic stroke (AIS) in the young. DESIGN. SETTING, AND PATIENTS: We studied 118 young patients (age, <45 years) with a first nonfatal AIS of undetermined etiology and 118 control subjects, matched simultaneously for age and sex. The PON1 C(-107)T polymorphism was determined by single-stranded conformational polymorphism analysis and the G(-824)A substitution by polymerase chain reaction and restriction enzyme digestion. RESULTS: The presence of the low-expressor -107T allele was associated with an independent increase in overall risk of AIS (odds ratio [OR], 2.69; 95% confidence interval [CI], 1.06-6.78; P =.04) by conditional multiple logistic regression analysis. Among individuals with the 192RR genotype, the presence of the -107T allele led to a higher but nonsignificant risk, yielding an OR of 4.15 (95% CI, 0.35-48.76; P =.15) when compared with noncarriers of the T allele and 17.01 (95% CI, 1.74-166.35; P =.02) when compared with noncarriers of either variant. No significant difference between groups was found regarding the G(-824)A polymorphism. CONCLUSION: These findings suggest that the PON1 -107T allele is independently associated with the risk of AIS, in addition to interacting with and potentiating the risk conferred by the Q192R polymorphism.

A genome-wide association meta-analysis of preschool internalizing problems.

OBJECTIVE: Preschool internalizing problems (INT) are highly heritable and moderately genetically stable from childhood into adulthood. Gene-finding studies are scarce. In this study, the influence of genome-wide measured single nucleotide polymorphisms (SNPs) was investigated in 3 cohorts (total N = 4,596 children) in which INT was assessed with the same instrument, the Child Behavior Checklist (CBCL). METHOD: First, genome-wide association (GWA) results were used for density estimation and genome-wide complex trait analysis (GCTA) to calculate the variance explained by all SNPs. Next, a fixed-effect inverse variance meta-analysis of the 3 GWA analyses was carried out. Finally, the overlap in results with prior GWA studies of childhood and adulthood psychiatric disorders and treatment responses was tested by examining whether SNPs associated with these traits jointly showed a significant signal for INT. RESULTS: Genome-wide SNPs explained 13% to 43% of the total variance. This indicates that the genetic architecture of INT mirrors the polygenic model underlying adult psychiatric traits. The meta-analysis did not yield a genome-wide significant signal but was suggestive for the PCSK2 gene located on chromosome 20p12.1. SNPs associated with other psychiatric disorders appeared to be enriched for signals with INT (λ = 1.26, p < .03). CONCLUSION: Our study provides evidence that INT is influenced by many common genetic variants, each with a very small effect, and that, even as early as age 3, genetic variants influencing INT overlap with variants that play a role in childhood and adulthood psychiatric disorders.

GWAS of 126,559 individuals identifies genetic variants associated with educational attainment.

A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.

Methods: genetic epidemiology.

Given the potential benefits of gene identification in psychiatry, genetic epidemiology has become a mainstream discipline within the field. This article discusses the main tools for gene discovery. The focus is on the designs and analytic approaches for each of these methods. Because most gene discovery has now moved to genetic association studies, and most recently to genome-wide association studies, the focus is on methods for this design. Also highlighted are the current challenges of genetic epidemiology as a prelude to future approaches that may be applied to psychiatric disorders in the coming years.

Methods: genetic epidemiology.

Given the potential benefits of gene identification in psychiatry, genetic epidemiology has become a mainstream discipline within the field. This article discusses the main tools for gene discovery. The focus is on the designs and analytic approaches for each of these methods. Because most gene discovery has now moved to genetic association studies, and most recently to genome-wide association studies, the focus is on methods for this design. Also highlighted are the current challenges of genetic epidemiology as a prelude to future approaches that may be applied to psychiatric disorders in the coming years.

Predictors of subjective memory complaint in cognitively normal relatives of patients with Alzheimer's disease.

The authors utilized a family-based, case-control study to identify factors predicting subjective memory complaint in relatives of Alzheimer's disease patients. The authors ascertained 1,499 cognitively healthy relatives of Alzheimer's disease patients at 15 centers, who contributed demographic and medical information, including self-assessment of memory. First-degree relatives of Alzheimer's disease patients reported subjective memory complaint more than spouses of Alzheimer's disease patients. Relatives with past depression symptoms endorsed subjective memory complaint more than those without such history. Clinicians counseling family members of Alzheimer's disease patients who express subjective memory complaint should first evaluate cognition. If cognition is intact, depression should be considered.

Risk of dementia among white and African American relatives of patients with Alzheimer disease.

CONTEXT: Evidence exists that the incidence of Alzheimer disease (AD), as well as risk attributable to specific genetic factors such as apolipoprotein E (APOE) genotype, may vary considerably among ethnic groups. Family studies of probands with AD offer an opportunity to evaluate lifetime risk of dementia among relatives of these probands. OBJECTIVE: To compare lifetime dementia risk estimates among relatives of white and African American probands with probable or definite AD. DESIGN AND SETTING: Risk analysis using data collected by questionnaire and supplemental records between May 1991 and March 2001 at 17 medical centers contributing to the Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study. PARTICIPANTS: A total of 17 639 first-degree biological relatives and 2474 spouses of 2339 white AD probands, and 2281 first-degree biological relatives and 257 spouses of 255 African American AD probands. MAIN OUTCOME MEASURES: Cumulative risk of dementia by age 85 years, stratified by ethnicity and sex of relatives and by APOE genotype of probands. RESULTS: Cumulative risk of dementia in first-degree biological relatives of African American AD probands by age 85 years was 43.7% (SE, 3.1%), and the corresponding risk in first-degree biological relatives of white AD probands was 26.9% (SE, 0.8%), yielding a relative risk (RR) of 1.6 (95% confidence interval [CI], 1.4-1.9; P<.001). The risk in spouses of African American AD probands of 18.5% (SE, 8.4%) was also higher than the risk in white spouses of 10.4% (SE, 1.7%) but did not reach statistical significance (RR, 1.8; 95% CI, 0.5-6.0; P =.34), likely due to the smaller sample size of African Americans. The proportional increase in risk of dementia among white first-degree biological relatives compared with white spouses of 2.6 (95% CI, 2.1-3.2) was similar to that of 2.4 (95% CI, 1.3-4.4) in African American first-degree biological relatives compared with African American spouses. Female first-degree biological relatives of probands had a higher risk of developing dementia than did their male counterparts, among whites (31.2% vs 20.4%; RR, 1.5; 95% CI, 1.3-1.7; P<.001) as well as among African Americans, although this was not significant among African Americans (46.7% vs 40.1%; RR, 1.2; 95% CI, 0.9-1.7, P =.30). The patterns of risk among first-degree biological relatives stratified by APOE genotype of the probands were similar in white families and African American families. CONCLUSION: First-degree relatives of African Americans with AD have a higher cumulative risk of dementia than do those of whites with AD. However, in this study, the additional risk of dementia conferred by being a first-degree relative, by being female, or by the probability of having an APOE epsilon4 allele appeared similar in African American and white families. These data provide estimates of dementia risk that can be used to offer counseling to family members of patients with AD.