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ImportanceSubjective memory concern has long been considered a state-related indicator of impending cognitive decline or dementia. The possibility that subjective memory concern may itself be a heritable trait is largely ignored, yet such an association would substantially confound its use in clinical or research settings.ObjectiveTo assess the heritability and traitlike dimensions of subjective memory concern and its clinical correlates.Design, Setting, and ParticipantsThis longitudinal twin cohort study was conducted from 1967 to 2019 among male adults with a mean (SD) age of 37.75 (2.52) years to follow-up at mean ages of 56.15 (2.72), 61.50 (2.43), and 67.35 (2.57) years (hereafter, 38, 56, 62, and 67 years, respectively) in the Vietnam Era Twin Study of Aging. The study included a national community-dwelling sample with health, education, and lifestyle characteristics comparable to a general sample of US men in this age cohort. Participants were monozygotic and dizygotic twins randomly recruited from the Vietnam Era Twin Registry. Data were analyzed from May 2021 to December 2022.Main Outcomes and MeasuresMeasures included subjective memory concern at 4 time points; objective memory, depressive symptoms, and anxiety at the last 3 time points; negative emotionality (trait neuroticism) at age 56 years; polygenic risk scores (PRSs) for neuroticism, depression, and Alzheimer disease; APOE genotype; and parental history of dementia. Primary outcomes were heritability and correlations between subjective memory concern and other measures.ResultsThe sample included 1555 male adults examined at age 38 years, 520 at age 56 years (due to late introduction of subjective memory concern questions), 1199 at age 62 years, and 1192 at age 67 years. Phenotypically, subjective memory concerns were relatively stable over time. At age 56 years, subjective memory concern had larger correlations with depressive symptoms (r, 0.32; 95% CI, 0.21 to 0.42), anxiety (r, 0.36; 95% CI, 0.18 to 0.51), and neuroticism (r, 0.34; 95% CI, 0.26 to 0.41) than with objective memory (r, −0.24; 95% CI, −0.33 to −0.13). Phenotypic results were similar at ages 62 and 67 years. A best-fitting autoregressive twin model indicated that genetic influences on subjective memory concern accumulated and persisted over time (h2 = 0.26-0.34 from age 38-67 years). At age 56 years, genetic influences for subjective memory concern were moderately correlated with genetic influences for anxiety (r, 0.36; 95% CI, 0.18 to 0.51), negative emotionality (r, 0.51; 95% CI, 0.44-0.57), and depressive symptoms (r, 0.20; 95% CI, 0.10 to 0.29) as well as objective memory (r, −0.22; 95% CI, −0.30 to −0.14). Similar genetic correlations were seen at ages 62 and 67 years. The neuroticism PRS was associated with subjective memory concern at age 38 years (r, 0.10; 95% CI, 0.03. to 0.18) and age 67 years (r, 0.09; 95% CI, 0.01 to 0.16). Subjective memory concern was not associated with any Alzheimer disease risk measures.Conclusions and RelevanceThis cohort study found stable genetic influences underlying subjective memory concern dating back to age 38 years. Subjective memory concern had larger correlations with affect-related measures than with memory-related measures. Improving the utility of subjective memory concern as an indicator of impending cognitive decline and dementia may depend on isolating its statelike component from its traitlike component.

Importance Incidental findings (IFs) are unexpected abnormalities discovered during imaging and can range from normal anatomic variants to findings requiring urgent medical intervention. In the case of brain magnetic resonance imaging (MRI), reliable data about the prevalence and significance of IFs in the general population are limited, making it difficult to anticipate, communicate, and manage these findings. Objectives To determine the overall prevalence of IFs in brain MRI in the nonclinical pediatric population as well as the rates of specific findings and findings for which clinical referral is recommended. Design, setting, and participants This cohort study was based on the April 2019 release of baseline data from 11 810 children aged 9 to 10 years who were enrolled and completed baseline neuroimaging in the Adolescent Brain Cognitive Development (ABCD) study, the largest US population-based longitudinal observational study of brain development and child health, between September 1, 2016, and November 15, 2018. Participants were enrolled at 21 sites across the US designed to mirror the demographic characteristics of the US population. Baseline structural MRIs were centrally reviewed for IFs by board-certified neuroradiologists and findings were described and categorized (category 1, no abnormal findings; 2, no referral recommended; 3; consider referral; and 4, consider immediate referral). Children were enrolled through a broad school-based recruitment process in which all children of eligible age at selected schools were invited to participate. Exclusion criteria were severe sensory, intellectual, medical, or neurologic disorders that would preclude or interfere with study participation. During the enrollment process, demographic data were monitored to ensure that the study met targets for sex, socioeconomic, ethnic, and racial diversity. Data were analyzed from March 15, 2018, to November 20, 2020. Main outcomes and measures Percentage of children with IFs in each category and prevalence of specific IFs. Results A total of 11 679 children (52.1% boys, mean [SD] age, 9.9 [0.62] years) had interpretable baseline structural MRI results. Of these, 2464 participants (21.1%) had IFs, including 2013 children (17.2%) assigned to category 2, 431 (3.7%) assigned to category 3, and 20 (0.2%) assigned to category 4. Overall rates of IFs did not differ significantly between singleton and twin gestations or between monozygotic and dizygotic twins, but heritability analysis showed heritability for the presence or absence of IFs (h2 = 0.260; 95% CI, 0.135-0.387). Conclusions and relevance Incidental findings in brain MRI and findings with potential clinical significance are both common in the general pediatric population. By assessing IFs and concurrent developmental and health measures and following these findings over the longitudinal study course, the ABCD study has the potential to determine the significance of many common IFs.

Case-control association studies use genetic markers as putative etiologic risk factors. The approach is controversial and has tended to produce associations in neuropsychiatry that do not stand the test of time. We studied the processes that can bias the outcomes away from a true representation of the relationship between a genetic marker and a neuropsychiatric disorder. If conducted with care and mindfulness of the potential pitfalls, case-control association studies can be an important tool for psychiatric genetic research.

Importance We do not know whether the clinical criteria for major depression (MD) reflect a single or multiple dimensions of genetic risk. Objective To determine the structure of genetic and environmental risk factors for the 9 DSM-IV symptomatic MD criteria. Design Population-based twin registry. Setting Virginia. Participants Seven thousand five hundred members of adult twin pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. Main Outcome Measure Symptoms of lifetime MD as assessed at personal interview. Results The best-fit twin model was multidimensional, requiring 3 genetic, 1 common environmental and 3 unique environmental common factors, and criterion-specific unique environmental factors. The first genetic factor was characterized by high loadings on cognitive and psychomotor depressive symptoms. The second and third genetic factors had strong loadings for mood and neurovegetative depressive symptoms, respectively. Genetic factor scores derived from these 3 factors differentially predicted patterns of comorbidity, other historical/clinical features of MD, and demographic variables. These results suggested that the first genetic factor reflected a general liability to internalizing disorders, while the third genetic factor was more specific for melancholic MD. The 3 unique environmental common factors reflected, respectively, global depressive, core mood, and cognitive depressive symptoms. Conclusions and Relevance The DSM-IV syndrome of MD does not reflect a single dimension of genetic liability. Rather, these criteria reflect 3 underlying dimensions that index genetic risk for cognitive/psychomotor, mood, and neurovegetative symptoms. While in need of replication, these results, validated by predictions using estimated genetic factor scores, have implications for gene-finding efforts for MD.

In their recent article, Hong et al1 reported heritabilities of auditory sensory gating. As they defined it in their article, heritability reflects the proportion of overall variability in a trait in a population that results from additive genetic effects. Within human populations, such estimates have traditionally relied on special relationships that can (with some well-understood limitations) disentangle genetic from familial-environmental effects. The most popular of these methods have been twin studies comparing monozygotic and dizygotic twin pairs and various adoption designs. However, in their study, Hong et al do not use these standard approaches. Rather, they examine individuals with schizophrenia (n=102) and 74 of their first-degree relatives. Heritabilities are estimated from sibling-sibling and parent-offspring pairs using the program SOLAR.2 The problem with this approach is that data from these 2 relationships alone do not contain information that can, with any confidence, disentangle genetic from familial-environmental sources of resemblance. This is because for the major source of genetic resemblance—additive genetic effects—the expected correlation is the same in both of these relationships: +0.50. It is true that nonadditive genetic effects contribute to sib-sib but not to parent-offspring resemblance. However, given that there may be considerable sharing of environmental factors for both of these relationships, the a priori assumption that their effects are absent is hard to justify for many phenotypes. We do not herein claim that heritability estimates from twin or adoption studies are without concerns. But they are based on well-understood quantitative genetic principles and their limitations have been widely examined (see Kendler and Prescott3 for concerns about the twin method). In studies such as that of Hong et al based only on first-degree relatives, we suggest that it would be advisable to use a more generic term such as transmissibility or familiality rather than the more specific term heritability.

Background: Patterns of comorbidity suggest that the common psychiatric and substance use syndromes may be divisible into 2 broad groups of internalizing and externalizing disorders. We do not know how genetic and environmental risk factors contribute to this pattern of comorbidity or whether the etiologic structure of these groups differ in men and women. Methods: Lifetime diagnoses for 10 psychiatric syndromes were obtained at a personal interview in more than 5600 members of male-male and female-female twin pairs ascertained from a population-based registry. Multivariate twin modeling was performed using the program Mx. Results: We first fit models to the following 7 syndromes: major depression, generalized anxiety disorder, phobia, alcohol dependence, drug abuse/dependence, adult antisocial behavior, and conduct disorder. The full model, which could be constrained to equality in male and female subjects, identified 2 genetic factors. The first had strongest loadings on alcohol dependence, drug abuse/dependence, adult antisocial behavior, and conduct disorder; the second, on major depression, generalized anxiety disorder, and phobia. Alcohol dependence and drug abuse/dependence had substantial disorder-specific genetic risk factors. Shared environmental factors were most pronounced for conduct disorder and adult antisocial behavior. No clear internalizing/externalizing structure was seen for the unique environmental common factors. We then fit models to 5 internalizing syndromes. The full model, which could also be constrained to equality in men and women, revealed one genetic factor loading most heavily on major depression and generalized anxiety disorder and another loading most strongly on animal and situational phobia. Conclusions: The underlying structure of the genetic and environmental risk factors for the common psychiatric and drug abuse disorders in men and women is very similar. Genetic risk factors predispose to 2 broad groups of internalizing and externalizing disorders. Within the internalizing disorders, 2 genetic factors are seen that predispose to disorders dominated by anxious-misery and fear. Substance use disorders have disorder-specific genetic risks. The externalizing disorders of conduct disorder and adult antisocial behavior are significantly influenced by the shared environment. The pattern of lifetime comorbidity of common psychiatric and substance use disorders results largely from the effects of genetic risk factors. Arch Gen Psychiatry. 2003;60:929-937

Background Much of our knowledge of the role of genetic factors in the etiology of phobias comes from one population-based sample of female twins. We examined the sources of individual differences in the risks for phobias and their associated irrational fears in male twins. Methods In personal interviews with both members of 1198 male-male twin pairs (707 monozygotic [MZ] and 491 dizygotic [DZ]) ascertained from a population-based registry, we assessed the lifetime history of agoraphobia and social, animal, situational, and blood/injury phobias as well as their associated irrational fears. Twin resemblance was assessed by means of probandwise concordance, odds ratios, tetrachoric correlations, and univariate and multivariate biometrical model fitting. Results The suggestive results obtained by analysis of phobias only were supported by analyzing both fears and phobias. All 5 phobia subtypes aggregate within twinpairs. This aggregation is due largely or solely to genetic factors with heritability of liabilities ranging from 25% to 37%. Multivariate analysis revealed a common genetic factor, genetic factors specific to each subtype, and a common familial-environmental factor. Conclusions In male subjects, genetic risk factors, which are partially common across all subtypes and partially subtype specific, play a moderate role in the etiology of phobias and their associated irrational fears. Family environment probably has an impact on risk for agoraphobia and social phobia. The genetic liability to blood/injury phobias is not distinct from those of the more typical phobias.

Background In order to develop informed approaches to prevention and treatment of illicit psychoactive substance use, abuse, and dependence, we need to understand the sources of individual differences in risk. Methods In personal interviews with 1198 male-male twin pairs (708 monozygotic and 490 dizygotic) ascertained from a population-based registry, we assessed lifetime use, heavy use, and abuse of and dependence on cannabis, sedatives, stimulants, cocaine, opiates, and hallucinogens. Twin resemblance was assessed by probandwise concordance, odds ratio, tetrachoric correlations, and biometrical model fitting. Results Twin resemblance for substance use, heavy use, abuse, and dependence was substantial, and consistently greater in monozygotic than in dizygotic twins. For any drug use and for cannabis and hallucinogen use, model fitting suggested that twin resemblance was due to both genetic and familial-environmental factors. Twin resemblance for sedative, stimulant, cocaine, and opiate use, however, was caused solely by genetic factors. With 2 exceptions (cocaine abuse and stimulant dependence), twin resemblance for heavy use, abuse, and dependence resulted from only genetic factors, with heritability of liability usually ranging from 60% to 80%. No consistent evidence was found for violations of the equal environment assumption. Conclusions In accord with prior results in studies of women, the family environment plays a role in twin resemblance for some forms of substance use in men. However, twin resemblance for heavy use, abuse, and dependence in men is largely caused by genetic factors, and heritability estimates are high.

Background: Temperance boards were established in Sweden to register and follow up individuals who were seen in legal or medical settings with problems of alcohol abuse. These records, available in a large epidemiologic twin population, have provided an objective and validated measure of alcohol abuse. Methods: We examined Swedish temperance board registrations from 1929 to 1974 (n=2516 individual twins) in all male-male Swedish twin pairs of known zygosity from the population-based Swedish Twin Registry; these twin pairs were born from 1902 to 1949 (n=8935 pairs). Results: The lifetime prevalence and probandwise concordance rates for temperance board registrations were 13.2% and 47.9%, respectively, in monozygotic twins and 14.6% and 32.8%, respectively, in dizygotic twins. Model fitting suggested that genetic and familial-environmental risk factors accounted for 54% (95% confidence interval [CI], 47%-61%) and 14% (95% CI, 8%-19%) of the liability to temperance board registration, respectively; these estimates were stable across birth cohorts. High genetic liability was reflected by large numbers of temperance board registrations and registrations for criminal alcohol use. Elevated familial-environmental liability was indicated by an early age at first registration. Conclusions: Genetic factors are of major etiologic importance for alcohol abuse in men, while familialenvironmental factors play a significant but less important role. The etiologic importance of these factors has remained constant in Sweden for men who were born in the first half of the 20th century.

Objectives: This study seeks to clarify the etiologic importance and temporal stability of the genetic and environmental risk factors for 1-year prevalence of major depression (1YP-MD) in women. Design: One-year prevalence of major depression was personally assessed, using DSM-III-R criteria, at two time points a minimum of 1 year apart. Participants: Both members of 938 adult femalefemale twin pairs ascertained from the population-based Virginia Twin Registry. Results: The correlation in liability to 1YP-MD was much greater in monozygotic (MZ) than in dizygotic (DZ) twins at time 1 alone, time 2 alone, or at either time 1 or time 2. Model fitting suggested that the liability to 1YP-MD was due to additive genes and individual specific envi- ronment with a heritability of 41% to 46% and was not biased by violations of the equal environment assumption. Jointly analyzing both times of assessment using a longitudinal twin model suggested that, over a 1-year period, genetic effects on the liability to 1YP-MD were entirely stable, while environmental effects were entirely occasion specific. Conclusions: These results suggest that (1) genetic factors play a moderate etiologic role in the 1YP-MD, (2) the temporal stability of the liability to major depression in adult women is largely or entirely genetic in origin, and (3) environmental factors play a significant role in the etiology of major depression, but their effects are generally transitory and do not result in enduring changes in the liability to illness.

Objectives: To examine the role of genetic and familialenvironmental factors in the origin of stressful life events. Design: Self-report questionnaires describing stressful life events in the last year. Participants: Both members of 2315 twin pairs ascertained from the population-based Virginia Twin Registry. Results: Life events were modestly but significantly correlated in twin pairs, and correlations in monozygotic (MZ) twins consistently exceeded those in dizygotic (DZ) twins. For total life events, the best-fitting twin model indicated that familial-environmental and genetic factors each accounted for around 20% of the total variance. Individual life events could be best divided into "network events" (directly affecting individuals in the respondent's socialnetwork) where twin resemblance was due solely to the familial environment, and "personal" events (directly affecting the response) where most twin resemblance was the result of genetic factors. Conclusions: While neither genes nor familial environment is likely to directly produce life events, personal and social factors that predispose to life events are substantially influenced by an individual's genetic and family background. These results, which suggest that stressful life events reflect more than random influences, may have important implications for our understanding of the relationship between stressful life events and psychopathology.

• Homosexual female probands with monozygotic cotwins, dizygotic cotwins, or adoptive sisters were recruited using homophile publications. Sexual orientation of relatives was assessed either by asking relatives directly, or, when this was impossible, by asking the probands. Of the relatives whose sexual orientation could be confidently rated, 34 (48%) of 71 monozygotic cotwins, six (16%) of 37 dizygotic cotwins, and two (6%) of 35 adoptive sisters were homosexual. Probands also reported 10(14%) nontwin biologic sisters to be homosexual, although those sisters were not contacted to confirm their orientations. Heritabilities were significant using a wide range of assumptions about both the base rate of homosexuality in the population and ascertainment bias. The likelihood that a monozygotic cotwin would also be homosexual was unrelated to measured characteristics of the proband such as self-reported history of childhood gender nonconformity. Concordant monozygotic twins reported similar levels of childhood gender nonconformity.

Objective. —To clarify the role of genetic factors in the etiology of alcoholism in women. Design and Setting. —Personal structured psychiatric interviews conducted by researchers "blinded" to the status of the co-twin in an epidemiologic sample of 1030 female-female twin pairs of known zygosity from the population-based Virginia Twin Registry. Measures. —Three definitions of lifetime prevalence of alcoholism based on Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised criteria: (1) alcoholism with tolerance or dependence; (2) alcoholism with or without tolerance-dependence; and (3) alcoholism with or without tolerance-dependence or problem drinking. Results. —Using narrow, intermediate, or broad definitions, the probandwise concordance for alcoholism was consistently higher in monozygotic than in dizygotic twin pairs. Multifactorial threshold models suggested that the heritability of liability to alcoholism in women is in the range of 50% to 60%. Conclusions. —The results support the hypothesis that genetic factors play a major role in the etiology of alcoholism in women. Women should be well represented in the efforts currently under way to elucidate the molecular basis of the genetic susceptibility to alcoholism. ( JAMA . 1992;268:1877-1882)

• Bivariate twin analysis can determine the extent to which two disorders share common genetic, familial environmental, or individual-specific environmental risk factors. We applied this method to lifetime diagnoses of major depression and generalized anxiety disorder as assessed at personal interview in a population-based sample of 1033 pairs of female same-sex twins. Three definitions of generalized anxiety disorder were used that varied in minimum duration (1 vs 6 months) and in the presence or absence of a diagnostic hierarchy. For all definitions of generalized anxiety disorder, the best-fitting twin model was the same. Familial environment played no role in the etiology of either condition. Genetic factors were important for both major depression and generalized anxiety disorder and were completely shared between the two disorders. A modest proportion of the nonfamilial environmental risk factors were shared between major depression and generalized anxiety disorder. Within the limits of our statistical power, our findings suggest that in women, the liability to major depression and generalized anxiety disorder is influenced by the same genetic factors, so that whether a vulnerable woman develops major depression or generalized anxiety disorder is a result of her environmental experiences.

• Little is known about the role of familial and genetic factors in the etiology of generalized anxiety disorder (GAD), a new disorder first proposed in DSM-III . We examine this question in 1033 female-female twin pairs from a population-based registry. Both members in each twin pair were "blindly" assessed by structured psychiatric interview. Our results suggest the following: (1) GAD is a moderately familial disorder; (2) the tendency for GAD to run in families seems to be due largely or entirely to genetic factors shared between relatives rather than to the effects of the familial environment; (3) the heritability of GAD, estimated at around 30%, is modest, with the remainder of the variance in liability resulting from environmental factors not shared by adult twins; (4) the heritability of GAD cannot be explained solely by the occurrence of GAD only during episodes of major depression or panic disorder; and (5) the etiologic role of genetic factors is probably similar in GAD with a 1- vs a 6-month minimum duration of illness.

Although depression aggregates in families, the degree to which this aggregation results from genetic vs environmental factors remains uncertain. We examined this question in 1033 female-female twin pairs from a population-based registry. Both members of each twin pair were "blindly" assessed by structured psychiatric interview. Nine commonly used definitions of major depression, which produced life-time prevalence rates ranging from 12% to 33%, were examined. For all definitions, the results of model fitting to twin correlations suggested that the liability to depression results from genetic factors and environmental experiences unique to the individual. For seven of the definitions, the estimated heritability of liability was similar, ranging from 33% to 45%. For the two definitions that included only primary cases of depression, the heritability was lower (21% to 24%). The results document that in women (1) genetic factors play a substantial, but not overwhelming, role in the cause of depression; (2) the tendency for depression to aggregate in families results largely from shared genetic and not from shared environmental factors; (3) except for definitions that exclude secondary cases, the magnitude of genetic influence is similar in broadly and narrowly defined forms of major depression; and (4) most environmental experiences of causative importance for depression are those not shared by members of an adult twin pair.