The use of direct-to-consumer genomewide profiling to assess disease risk is controversial, and little is known about the effect of this technology on consumers. We examined the psychological, behavioral, and clinical effects of risk scanning with the Navigenics Health Compass, a commercially available test of uncertain clinical validity and utility.
We recruited subjects from health and technology companies who elected to purchase the Health Compass at a discounted rate. Subjects reported any changes in symptoms of anxiety, intake of dietary fat, and exercise behavior at a mean (±SD) of 5.6±2.4 months after testing, as compared with baseline, along with any test-related distress and the use of health-screening tests.
From a cohort of 3639 enrolled subjects, 2037 completed follow-up. Primary analyses showed no significant differences between baseline and follow-up in anxiety symptoms (P = 0.80), dietary fat intake (P = 0.89), or exercise behavior (P = 0.61). Secondary analyses revealed that test-related distress was positively correlated with the average estimated lifetime risk among all the assessed conditions (β = 0.117, P<0.001). However, 90.3% of subjects who completed follow-up had scores indicating no test-related distress. There was no significant increase in the rate of use of screening tests associated with genomewide profiling, most of which are not considered appropriate for screening asymptomatic persons in any case.
In a selected sample of subjects who completed follow-up after undergoing consumer genomewide testing, such testing did not result in any measurable short-term changes in psychological health, diet or exercise behavior, or use of screening tests. Potential effects of this type of genetic testing on the population at large are not known. (Funded by the National Institutes of Health and Scripps Health.)
HIV-associated sensory neuropathy remains an important complication of combination antiretroviral therapy (CART) and HIV infection. Mitochondrial DNA haplogroups and single nucleotide polymorphisms (SNPs) have previously been associated with symptomatic neuropathy in clinical trial participants. We examined associations between mitochondrial DNA variation and HIV-associated sensory neuropathy in CHARTER. CHARTER is a U.S. based longitudinal observational study of HIV-infected adults who underwent a structured interview and standardized examination. HIV-associated sensory neuropathy was determined by trained examiners as ≥1 sign (diminished vibratory and sharp-dull discrimination or ankle reflexes) bilaterally. Mitochondrial DNA sequencing was performed and haplogroups were assigned by published algorithms. Multivariable logistic regression of associations between mitochondrial DNA SNPs, haplogroups and HIV-associated sensory neuropathy were performed. In analyses of associations of each mitochondrial DNA SNP with HIV-associated sensory neuropathy, the two most significant SNPs were at positions A12810G (odds ratio [95% confidence interval] = 0.27 [0.11-0.65]; p = 0.004) and T489C (odds ratio [95% confidence interval] = 0.41 [0.21-0.80]; p = 0.009). These synonymous changes are known to define African haplogroup L1c and European haplogroup J, respectively. Both haplogroups are associated with decreased prevalence of HIV-associated sensory neuropathy compared with all other haplogroups (odds ratio [95% confidence interval] = 0.29 [0.12-0.71]; p = 0.007 and odds ratio [95% confidence interval] = 0.42 [0.18-1.0]; p = 0.05, respectively). In conclusion, in this cohort of mostly combination antiretroviral therapy-treated subjects, two common mitochondrial DNA SNPs and their corresponding haplogroups were associated with a markedly decreased prevalence of HIV-associated sensory neuropathy.
genetics; mitochondria; HIV-related neurological diseases; peripheral neuropathy
The ongoing controversy surrounding direct-to-consumer (DTC) personal genomic tests intensified last year when the U.S. Government Accountability Office (GAO) released results of an undercover investigation of four companies that offer such testing. Among their findings, they reported that some of their donors received DNA-based predictions that conflicted with their actual medical histories. We aimed to more rigorously evaluate the relationship between DTC genomic risk estimates and self-reported disease by leveraging data from the Scripps Genomic Health Initiative (SGHI). We prospectively collected self-reported personal and family health history data for 3,416 individuals who went on to purchase a commercially available DTC genomic test. For 5 out of 15 total conditions studied, we found that risk estimates from the test were significantly associated with self-reported family and/or personal health history. The 5 conditions, included Graves’ disease, Type 2 Diabetes, Lupus, Alzheimer’s disease, and Restless Leg Syndrome. To further investigate these findings, we ranked each of the 15 conditions based on published heritability estimates and conducted post-hoc power analyses based on the number of individuals in our sample who reported significant histories of each condition. We found that high heritability, coupled with high prevalence in our sample and thus adequate statistical power, explained the pattern of associations observed. Our study represents one of the first evaluations of the relationship between risk estimates from a commercially available DTC personal genomic test and self-reported health histories in the consumers of that test.
direct-to-consumer; genetic testing; genetic risk estimates; clinical validity; consumer genomics
Over the past 18 months, there have been notable developments in the direct-to-consumer (DTC) genomic testing arena, in particular with regard to issues surrounding governmental regulation in the USA. While commentaries continue to proliferate on this topic, actual empirical research remains relatively scant. In terms of DTC genomic testing for disease susceptibility, most of the research has centered on uptake, perceptions and attitudes toward testing among health care professionals and consumers. Only a few available studies have examined actual behavioral response among consumers, and we are not aware of any studies that have examined response to DTC genetic testing for ancestry or for drug response. We propose that further research in this area is desperately needed, despite challenges in designing appropriate studies given the rapid pace at which the field is evolving. Ultimately, DTC genomic testing for common markers and conditions is only a precursor to the eventual cost-effectiveness and wide availability of whole genome sequencing of individuals, although it remains unclear whether DTC genomic information will still be attainable. Either way, however, current knowledge needs to be extended and enhanced with respect to the delivery, impact and use of increasingly accurate and comprehensive individualized genomic data.
Follow-up studies of eating disorders (EDs) suggest outcomes ranging from recovery to chronic illness or death, but predictors of outcome have not been consistently identified. We tested 5151 single-nucleotide polymorphisms (SNPs) in approximately 350 candidate genes for association with recovery from ED in 1878 women. Initial analyses focused on a strictly defined discovery cohort of women who were over age 25 years, carried a lifetime diagnosis of an ED, and for whom data were available regarding the presence (n=361 ongoing symptoms in the past year, ie, ‘ill') or absence (n=115 no symptoms in the past year, ie, ‘recovered') of ED symptoms. An intronic SNP (rs17536211) in GABRG1 showed the strongest statistical evidence of association (p=4.63 × 10−6, false discovery rate (FDR)=0.021, odds ratio (OR)=0.46). We replicated these findings in a more liberally defined cohort of women age 25 years or younger (n=464 ill, n=107 recovered; p=0.0336, OR=0.68; combined sample p=4.57 × 10−6, FDR=0.0049, OR=0.55). Enrichment analyses revealed that GABA (γ-aminobutyric acid) SNPs were over-represented among SNPs associated at p<0.05 in both the discovery (Z=3.64, p=0.0003) and combined cohorts (Z=2.07, p=0.0388). In follow-up phenomic association analyses with a third independent cohort (n=154 ED cases, n=677 controls), rs17536211 was associated with trait anxiety (p=0.049), suggesting a possible mechanism through which this variant may influence ED outcome. These findings could provide new insights into the development of more effective interventions for the most treatment-resistant patients.
GABA; anorexia nervosa; recovery from eating disorders; genetic association; single nucleotide polymorphisms; eating/metabolic disorders; GABA; eating/metabolic disorders; neurogenetics; biological psychiatry; genetic association; anorexia nervosa; recovery from eating disorders; single-nucleotide polymorphisms; phenomic association
Individuals can now obtain their personal genomic information via direct-to-consumer genetic testing, but what, if any, impact will this have on their lifestyle and health? A recent longitudinal cohort study of individuals who underwent consumer genome scanning found minimal impacts of testing on risk-reducing lifestyle behaviors, such as diet and exercise. These results raise an important question: is personal genomic information likely to beneficially impact public health through motivation of lifestyle behavioral change? In this article, we review the literature on lifestyle behavioral change in response to genetic testing for common disease susceptibility variants. We find that only a few studies have been carried out, and that those that have been done have yielded little evidence to suggest that the mere provision of genetic information alone results in widespread changes in lifestyle health behaviors. We suggest that further study of this issue is needed, in particular studies that examine response to multiplex testing for multiple genetic markers and conditions. This will be critical as we anticipate the wide availability of whole-genome sequencing and more comprehensive phenotyping of individuals. We also note that while simple communication of genomic information and disease susceptibility may be sufficient to catalyze lifestyle changes in some highly motivated groups of individuals, for others, additional strategies may be required to prompt changes, including more sophisticated means of risk communication (e.g., in the context of social norm feedback) either alone or in combination with other promising interventions (e.g., real-time wireless health monitoring devices).
behavioral intervention; consumer genomics; direct-to-consumer; genetic risk; genetic testing; nudging; personalized medicine; social norm feedback; wireless monitoring
Cortical thickness is a highly heritable structural brain measurement and reduced thickness has been associated with both schizophrenia and bipolar disorder as well as decreased cognitive performance among healthy controls. Identifying genes that contribute to variation in cortical thickness provides a path to elucidate some of the biological mechanisms underlying these diseases as well as general cognitive abilities.
To identify common genetic variants that affect cortical thickness in schizophrenia, bipolar disorder, and controls and secondarily to test these variants for association with cognitive performance.
597,198 single nucleotide polymorphisms (SNPs) were tested for association with average cortical thickness in a genome-wide association study (GWAS). Significantly associated SNPs were tested for their affect on several measures of cognitive performance.
Four major hospitals in Oslo, Norway.
The GWAS included controls (n = 181) and individuals with DSM-IV diagnosed schizophrenia spectrum disorder (n = 94), bipolar spectrum disorder (n = 97), and other psychotic and affective disorders (n = 49). The follow-up cognitive study included an additional 622 cases and controls.
Main Outcome Measures
Cortical thickness measured with magnetic resonance imaging and cognitive performance as assessed by several neuropsychological tests.
Two closely linked genetic variants (rs4906844 and rs11633924) within the Prader-Willi/Angelman syndrome region on chromosome 15q12 showed genome-wide significant association (p = 1.08 × 10−8) with average cortical thickness as well as modest association with cognitive performance (p = 0.028) specifically among subjects diagnosed with schizophrenia.
This is the first GWAS to identify a common genetic variant that contributes to the heritable reduction of cortical thickness in schizophrenia. These results highlight the utility of cortical thickness as an intermediate phenotype for neuropsychiatric diseases. Future independent replication studies are required to confirm these findings.
This analysis is a follow-up to an earlier investigation of 182 genes selected as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN). As those initial case-control results revealed no statistically significant differences in single nucleotide polymorphisms, herein we investigate alternative phenotypes associated with AN. In 1762 females using regression analyses we examined: (1) lowest illness-related attained body mass index; (2) age at menarche; (3) drive for thinness; (4) body dissatisfaction; (5) trait anxiety; (6) concern over mistakes; and (7) the anticipatory worry and pessimism vs. uninhibited optimism subscale of the harm avoidance scale. After controlling for multiple comparisons, no statistically significant results emerged. Although results must be viewed in the context of limitations of statistical power, the approach illustrates a means of potentially identifying genetic variants conferring susceptibility to AN because less complex phenotypes associated with AN are more proximal to the genotype and may be influenced by fewer genes.
covariates; eating disorders; association studies; personality; genetic
Human aging is a complex, multifactorial process influenced by a number of genetic and non-genetic factors. This article first reviews genetic strategies for human aging research and considers the advantages and disadvantages of each. We then discuss the issue of phenotypic definition for genetic studies of aging, including longevity/life span, as well as disease-free survival and other endophenotypes. Finally, we argue that extensions of this area of research, including incorporation of gene × environment interactions, multivariate phenotypes, integration of functional genomic annotations, and exploitation of orthology – many of which are already initiated and ongoing – are critical to advancing this field.
The enormous advances in genetics and genomics of the past decade have the potential to revolutionize health care, including mental health care, and bring about a system predominantly characterized by the practice of genomic and personalized medicine. We briefly review the history of genetics and genomics and present heritability estimates for major chronic diseases of aging and neuropsychiatric disorders. We then assess the extent to which the results of genetic and genomic studies are currently being leveraged clinically for disease treatment and prevention and identify priority research areas in which further work is needed. Pharmacogenomics has emerged as one area of genomics that already has had notable impacts on disease treatment and the practice of medicine. Little evidence, however, for the clinical validity and utility of predictive testing based on genomic information is available, and thus has, to some extent, hindered broader-scale preventive efforts for common, complex diseases. Furthermore, although other disease areas have had greater success in identifying genetic factors responsible for various conditions, progress in identifying the genetic basis of neuropsychiatric diseases has lagged behind. We review social, economic, and policy issues relevant to genomic medicine, and find that a new model of health care based on proactive and preventive health planning and individualized treatment will require major advances in health care policy and administration. Specifically, incentives for relevant stakeholders are critical, as are realignment of incentives and education initiatives for physicians, and updates to pertinent legislation. Moreover, the translational behavioral and public health research necessary for fully integrating genomics into health care is lacking, and further work in these areas is needed. In short, while the pace of advances in genetic and genomic science and technology has been rapid, more work is needed to fully realize the potential for impacting disease treatment and prevention generally, and mental health specifically.
genomics; genetic testing; genetic risk assessment; public health genomics; pharmacogenomics
Extensive population-based genome-wide association studies have identified an association between the FTO gene and BMI; however, the mechanism of action is still unknown. To determine whether FTO may influence weight regulation through psychological and behavioral factors, seven single nucleotide polymorphisms (SNPs) of the FTO gene were genotyped in 1085 individuals with anorexia nervosa (AN) and 677 healthy weight controls from the international Price Foundation Genetic Studies of Eating Disorders. Each SNP was tested in association with eating disorder phenotypes and measures that have previously been associated with eating behavior pathology: trait anxiety, harm-avoidance, novelty seeking, impulsivity, obsessionality, compulsivity, and concern over mistakes. After appropriate correction for multiple comparisons, no significant associations between individual FTO gene SNPs and eating disorder phenotypes or related eating behavior pathology were identified in cases or controls. Thus, this study found no evidence that FTO gene variants associated with weight regulation in the general population are associated with eating disorder phenotypes in AN participants or matched controls.
Although a highly heritable and disabling disease, bipolar disorder's (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5×10−7). To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. These results indicate that there is likely common genetic variation associated with BD near exons (±10 kb) that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies.
Bipolar disorder (BD) is a highly heritable disease that has been difficult to characterize genetically. We have genotyped 1,190 BD cases and 401 controls to find regions of the genome associated with BD. After combining these data with previously existing genotyped samples, we did not find any genome-wide significant associations. However, when we used an additional study to prioritize loci for replication and meta-analysis purposes, we found that we were more likely to see an association in our sample with variants for which we had the highest power. We quantified this effect using logistic regression and saw a strong association between power to detect an effect based on an initial study's results and replication P-value in a second study (P = 1.5×10−7), supporting the presence of shared genetic risk factors across the studies. Moreover, this association was stronger when we restricted analysis to SNPs near coding regions, and it was further enriched when SNPs had the same direction of effect in both studies. This result supports the presence of genetic factors underlying BD near exons whose collective effect results in a detectable signal and provides a framework for assessing the potential for replication when combining results from multiple studies.
We sought to investigate whether APOE genotype is associated with unique profiles of cognitive functioning during early life. School-aged children (N = 147) received standardized achievement tests, the Rey-Osterrieth Complex Figure Test (Copy Condition; RCFT-CC), assessment of hand dominance for writing, and buccal swab testing to determine their APOE genotype. Significant differences were found on the RCFT-CC, with ε2-positive children performing worse on this measure relative to both ε3/3 (p = .032) and ε4-positive children (p = .018). Further, a higher prevalence of left-hand dominance for writing was observed among ε2-positive children (29.2%) relative to ε3/3 (8.9%) and ε4-positive children (6.1%; p = .012), although this finding did not account for the observed group differences on the RCFT-CC. Findings raise the possibility that in childhood, the ε2 allele may be associated with (a) decreased functioning in certain cognitive domains; and (b) factors associated with atypical hemispheric dominance. Results may be consistent with the theory of antagonistic pleiotropy, which suggests that APOE may have different protective effects at different developmental stages.
Cognitive aging; neurodevelopment; apolipoprotein E; developmental neuropsychology; dementia; Alzheimer’s disease
To identify Bipolar Disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n = 1,001 cases; n = 1,033 controls) and one involving a sample of individuals of African ancestry (AA; n = 345 cases; n = 670 controls). For the EA sample, SNPs with strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (p = 1.6 × 10-6) and rs10193871 in NAP5 at 2q21.2 (p = 9.8 × 10-6). For the AA sample, SNPs with strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (p = 1.5 × 10-6) and rs2769605 in NTRK2 at 9q21.33 (p = 4.5 × 10-5). We also investigated whether we could provide support for three regions previously associated with BD, and we show that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects; SNPs with the strongest statistical evidence for this included rs11208285 in ROR1 at 1p31.3 (p = 1.4 × 10-6), rs4657247 in RGS5 at 1q23.3 (p = 4.1 × 10-6), and rs7078071 in BTBD16 at 10q26.13 (p = 4.5 × 10-6). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.
ANK3; C15Orf53; NAP5; DPY19L3; NTRK2; SLITRK2; ROR1; Bipolar Genome Study; Genetic Information Association Network (GAIN); genetic background; allelic heterogeneity
We performed association studies with 5,151 SNPs that were judged as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN) based on location under reported linkage peaks, previous results in the literature (182 candidate genes), brain expression, biological plausibility, and estrogen responsivity. We employed a case–control design that tested each SNP individually as well as haplotypes derived from these SNPs in 1,085 case individuals with AN diagnoses and 677 control individuals. We also performed separate association analyses using three increasingly restrictive case definitions for AN: all individuals with any subtype of AN (All AN: n = 1,085); individuals with AN with no binge eating behavior (AN with No Binge Eating: n = 687); and individuals with the restricting subtype of AN (Restricting AN: n = 421). After accounting for multiple comparisons, there were no statistically significant associations for any individual SNP or haplotype block with any definition of illness. These results underscore the importance of large samples to yield appropriate power to detect genotypic differences in individuals with AN and also motivate complementary approaches involving Genome-Wide Association (GWA) studies, Copy Number Variation (CNV) analyses, sequencing-based rare variant discovery assays, and pathway-based analysis in order to make up for deficiencies in traditional candidate gene approaches to AN.
single nucleotide polymorphisms; probands; anorexia nervosa; bulimia nervosa
The ε4 allele of the apolipoprotein E gene (APOE-ε4) and a family history (+FH) of Alzheimer’s disease (AD) are both risk factors for the development of AD. While studies to identify a preclinical phase of AD have led to evidence of APOE-ε4- and +FH-related differences in brain and cognitive functioning in healthy adults, the relative influence of these factors in children is unknown.
To investigate this issue, school-aged children (n = 109) received standardized achievement tests, the Rey-Osterrieth Complex Figure Test (Copy Condition; RCFT-CC), assessment of family medical history, and buccal swab testing to determine their APOE genotype.
Analyses revealed that, relative to children without these risk factors, children who possess both an APOE-ε4 allele and a +FH of AD and/or significant memory problems (MP) obtained lower scores on nearly every cognitive test administered.
Findings suggest that when both AD risk factors are present, cognition may be adversely impacted as early as childhood. Thus, risk factors for a disorder of pathological aging (i.e., AD) may have implications for the etiology of certain types of learning difficulties in children.
Alzheimer’s disease; apolipoprotein E; cognition; children; learning disorders; cognitive reserve
An overall burden of rare structural genomic variants has not been reported in Bipolar Disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix SNP 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kilobases in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation p = 0.007). This effect was more pronounced for age at onset of mania ≤ 18 years old. Our results strongly suggest that BD can result from the effects of multiple rare structural variants.