Search

Verbal declarative memory deficits in schizophrenia are well documented whereas visual declarative memory is less studied. Moreover, there are limited data on whether organizational and visual memory deficits are specific to schizophrenic psychoses. We compared visual memory and organizational function in patients with chronic schizophrenia (n=79) and chronic bipolar psychotic disorder (n=14), and in healthy controls (n=84) using the Rey-Osterrieth Complex Figure (ROCF), testing whether organizational impairments (i.e., executive dysfunctions) account for the visual memory deficit. Groups were comparable on age, handedness and expected intellectual ability (based on single word reading). Using analyses of covariance with sex, parental SES and ethnicity as co-variates, patients with schizophrenia were significantly more impaired than controls on copy accuracy, on recall accuracy, and on percent accuracy of recall. Patients with schizophrenia used a more detail-oriented style on copy and recall and had significantly worse recognition memory. After co-varying IQ, copy organization was also significantly different between the groups. Results for accuracy of copy and recall were not significantly attenuated when controlling for copy organization. Duration of illness was associated with visual memory. Bipolar patients performed at an intermediate level between controls and patients with schizophrenia. The data suggest that in schizophrenia, patients have a visual memory disorder characterized by both organizational processing impairments and retention difficulties, and that there is a decline in visual memory functions with duration of illness. Further research is required to determine whether similar mechanisms underlie the neurocognitive deficits in these psychotic disorders.

The corpus callosum (CC) has been of interest in schizophrenia research because of its possible role in reduced lateralization and because of its sexually dimorphic characteristics. The literature has been replete with structural brain studies that have yielded equivocal results because of failure to address sex differences, handedness, and overall reductions in total brain volume (TBV) associated with schizophrenia. We performed midsagittal corpus callosum area MRI measurements on 71 chronically ill patients with schizophrenia (52 males, 19 females) and 67 controls (49 males, 18 females) using a semiautomated analytic technique subdividing the corpus callosum into five segments. Consistent with a meta-analysis [J. Neurol., Neurosurg. Psychiatry 58 (1995) 457], reductions in total CC area (after controlling for TBV and age) were found in schizophrenia patients relative to controls. However, our effect size, though not statistically significant, was -0.33 compared to -0.18 for the meta-analysis, indicating greater reductions in total CC area in our group of patients. Statistical significance was achieved only in male patients versus male controls (effect size=-0.50). The effect size remained the same when only right-handers were included in the analysis; thus, handedness did not account for this result. CC size was not related to psychiatric symptoms nor cognitive functioning in this group of patients.

Phonemic and semantic fluency involve the capacity to generate words beginning with particular letters or belonging to particular categories, respectively. The former has been associated with frontal lobe function and the latter with temporoparietal function, but neuroimaging studies indicate overlap of underlying neural networks. Schizophrenia patients may experience disproportionate semantic fluency impairment owing to abnormal semantic organization; however, executive dysfunction in schizophrenia suggests possible disproportionate phonemic fluency impairment. Moreover, little is known about the diagnostic specificity of either verbal fluency deficit to schizophrenia or their stability over time. We examined 83 schizophrenia patients, 15 bipolar disorder patients, and 83 normal controls. Both fluency types were impaired in schizophrenia patients. Schizophrenia patients as a whole manifested disproportionate semantic fluency impairment relative to bipolar disorder patients, but only a subset of schizophrenia patients manifested disproportionate semantic fluency impairment relative to controls. Few characteristics, except to some extent paranoid-nonparanoid subtype, meaningfully differentiated schizophrenia patients with and without this disproportionate impairment. Verbal fluency measures were moderately stable over a 4-year period in schizophrenia patients and controls (.48 < rs < .79). These results mirror a literature that overall suggests a small degree of disproportionate semantic fluency impairment in schizophrenia, but also some heterogeneity in fluency deficits. (JINS, 2003, 9, 79–88.)

Age-related changes in testosterone are believed to be a key component of the processes that contribute to cognitive aging in men. The APOE-ε4 allele may interact with testosterone and moderate the hormone's association with cognition. The goals of the present study were to examine the degree to which free testosterone is associated with episodic memory in a community-based sample of middle-aged men, and examine the potential interaction between free testosterone and the APOE-ε4 allele. Data were used from 717 participants in the Vietnam Era Twin Study of Aging. Average age was 55.4 years (standard deviation = 2.5). Significant positive associations were observed between free testosterone level and verbal episodic memory, as well as a significant interaction between free testosterone and APOE-ε4 status. In ε4 carriers free testosterone was positively associated with verbal episodic memory performance (story recall), whereas no association was observed in ε4 noncarriers. Results support the hypothesis that APOE-ε4 status increases susceptibility to other risk factors, such as low testosterone, which may ultimately contribute to cognitive decline or dementia.

OBJECTIVE: This study sought to determine the relationship of estrogen levels with psychiatric symptoms and neuropsychological function in female patients with schizophrenia. METHOD: Psychiatric symptoms were assessed and average estrogen and progesterone levels from four consecutive weekly blood samples were measured in 22 female inpatients with schizophrenia who were also administered a neuropsychological battery. RESULTS: There were strong positive correlations between average estrogen level and cognitive function, especially measures of global cognitive function, verbal and spatial declarative memory, and perceptual-motor speed. Correlations of hormone levels with psychiatric symptoms were nonsignificant. CONCLUSIONS: Higher estrogen levels in female patients with schizophrenia are associated with better cognitive ability. These results may have implications for potential treatment of cognitive dysfunction with adjunctive estrogen in female patients with schizophrenia.

A leading hypothesis suggests that schizophrenic patients suffer from a disconnection syndrome. A failure in functional connectivity curtails the cortical integration and network activation needed to perform working memory tasks. Simulations with neural network models also indicate that connectivity is crucial for simulation of working memory asks. Multichannel EEG correlation-coefficient estimations are considered as a reliable measurement of connectivity patterns among cortical regions. In this study EEG samples are obtained selectively at the delay epochs of a delayed response working memory task. Results of correlation-coefficient estimations indicate a lack of statistically significant changes between non-task and task conditions in frontal, certain parietal, temporal and central channels. These findings propose that schizophrenics probably "fail" to activate the neural networks of the fronto-temporal regions. These are the networks involved in computation of the working memory task. Interestingly also good performers schizophrenics failed to activate these networks suggesting that the connectivity function is more relevant to the disorder than to task performance. If distinct deficits in cortical network activations would correlate with mental disorders it would be relevant to diagnosis and treatment of psychiatric disorders.

Background: We previously reported that the nonpsychotic relatives of schizophrenic patients exhibited disturbances in executive functioning, verbal and visual memory, auditory attention, mental control, and verbal ability. In a 4-year follow-up, we showed that the discriminating power of most of these tests was stable over time. Methods: In this report we compare 41 nonpsychotic persons who have only one schizophrenic first-degree relative (simplex families) with 36 nonpsychotic persons who have two schizophrenic first-degree relatives (multiplex families). Our goal was to test a hypothesis that neuropsychologic deficits would be worse among the latter. Results: Relatives from multiplex families differed significantly from controls on estimated intelligence, immediate and delayed logical memories, and immediate visual reproductions. In contrast, in comparisons with controls, relatives from simplex families only differed on immediate logical memories. Comparisons between relatives from multiplex and simplex families showed that the former group had significantly worse scores for estimated intelligence, immediate and delayed logical memories, and immediate visual reproductions. We also found group × gender interactions: the worse performance of the multiplex group was seen for females. Conclusions: These results are consistent with the idea that neuropsychologic deficits in relatives of schizophrenic patients reflect their degree of genetic predisposition to schizophrenia. They also suggest hypotheses about gender differences in the familial transmission of the disorder.

Evidence of subtle neuropsychological deficits in relatives of schizophrenic probands (REL-SZs) suggests that these are risk indicators for schizophrenia, but little is known about whether neuropsychological performance in REL-SZs differs from that in other groups of relatives. We compared neuropsychological function in female REL-SZs (n = 39), relatives of primarily psychotic bipolar disorder probands (REL-BPs; n = 15), and a normal control group (n = 44). After adjustment for expected intellectual ability (based on reading recognition), REL-SZs showed deficits in verbal and visual memory (Wechsler Memory Scale-Revised logical memories, visual reproductions), and auditory attention (dichotic digits) compared with either REL-BPs or control subjects. Memory, but not dichotic listening differences remained significant after adjusting for current IQ; however, average effect sizes after controlling for either reading or IQ were roughly comparable for these three parameters (d = 0.80, 0.71, and 0.69, respectively). REL-BPs and control subjects showed little difference. Although both schizophrenic and bipolar patients often manifest neuropsychological dysfunction, these preliminary findings indicate subtle neuropsychological deficits only in REL-SZs. Such differences suggest different underlying processes; neuropsychological impairment may, in part, reflect an expression of genetic liability to schizophrenia but not bipolar disorder. Replication with a larger REL-BP sample and with male relatives is needed to evaluate the generalizability of the results.

The goal of this study was to examine cognitive antecedents of psychosis by determining whether variability in IQ during childhood was predictive of psychotic symptoms in adulthood.Deviant responder analyses were used to examine prospectively the relationship of IQ at ages 4 and 7 to psychotic symptoms at age 23 in 547 offspring from a community sample (National Collaborative Perinatal Project) that was unselected for psychiatric illness. The authors compared three hypotheses: that 1) low IQ, 2) large IQ fluctuations regardless of direction, or 3) large IQ declines would predict the presence of adult psychotic symptoms.The 10% of individuals with substantially larger than expected IQ declines from age 4 to 7 had a rate of psychotic, but not other psychiatric, symptoms at age 23 that was nearly seven times as high as the rate for other persons. Parental socioeconomic status and IQ at age 7 also predicted adult psychotic symptoms. However, when IQ at age 7, IQ decline between ages 4 and 7, and socioeconomic status were all included in a logistic regression analysis, only IQ decline remained significant.There is an increased likelihood of developing psychotic symptoms in adulthood for a subgroup of individuals with substantially greater than expected IQ declines during childhood. IQ decline is specific for psychotic symptoms, but follow-up assessment when the study participants are further into the age of risk will be necessary to determine specificity for schizophrenia. The authors discuss the implications of this early cognitive downturn for a neurodevelopmental view of schizophrenia.

Objective: The factor structures of individual positive and negative symptoms as well as global ratings were examined in a diagnostically heterogeneous group of subjects. Method: Subjects were identified through a clinical and family study of patients with major psychoses at a VA medical center and evaluated with the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms. For the examination of global-level factor structures (N=630), both principal-component analysis and factor analysis with orthogonal rotation were used. Factor analysis was used for the examination of item-level factor structures as well (N=549). Results: The principal-component analysis of global ratings revealed three factors: negative symptoms, positive symptoms, and disorganization. The factor analysis of global ratings revealed a negative symptom factor and a positive symptom factor. The itemlevel factor analysis revealed two negative symptom factors (diminished expression and disordered relating), two positive symptom factors (bizarre delusions and auditory hallucinations), and a disorganization factor. Conclusions: The generation of additional meaningful factors at the item level suggests that important information about symptoms is lost when only global ratings are viewed. Future work should explore clinical and pathological correlates of the more differentiated item-level symptom dimensions. (Am J Psychiatry 1997; 154:371‐377)

We reviewed potential neuropsychological risk indicators for schizophrenia by addressing two broad questions about neuropsychological performance in biological relatives of schizophrenia patients: (1) Is there evidence of deficits, and, if so, (2) are those deficits similar to deficits found in schizophrenia patients themselves? There has not yet been adequate validation of most neuropsychological risk indicators, but promising leads have emerged from studies of relatives of persons with schizophrenia. The strongest evidence of impairment in relatives was in sustained attention, perceptual-motor speed, and concept formation and abstraction; to a slightly lesser extent, mental control/encoding (primarily with distraction) was implicated as well. Impairments in verbal memory and verbal fluency were also found, although these have been less well studied. The pattern of deficits paralleled that found in schizophrenia patients, thus suggesting dysfunction in prefrontal, temporal-limbic, and attentional systems. Findings were similar for children and adult relatives of schizophrenia patients. It is suggested that future studies (1) emphasize comprehensive test batteries, (2) develop composite neuropsychological measures, (3) use profile and deviant-responder analyses, (4) include psychiatric comparison groups, and (5) integrate neuropsychological assessments with brain imaging techniques.

The effect of 80%–90% neuroleptic dose reductions on neuropsychological function in schizophrenic and schizoaffective patients was examined in a prospective study. A neuropsychological battery was administered in the week prior to neuroleptic reduction followed by retesting at least 6 weeks postreduction. Patients were retested only if they did not relapse after reduction. The design allowed neuropsychological changes due to neuroleptic medications to be assessed independently of general clinical change. Neuropsychological performance was generally stable and unchanging. However, there was a trend toward significant improvement on a dichotic digits task based in improvement in left ear accuracy. Negative symptoms diminished after reduction. Compared with a normal control group, schizophrenics' initial laterality index showed a significantly exaggerated right ear advantage (REA); after reduction, the REA was no longer different from controls. The findings indicate that neuropsychological changes in a small sample of older nonrelapsing chronic schizophrenics are modest. The data suggest that neuroleptics may impair right hemisphere functions in some patients.

Chad A Bousman1, Gursharan Chana2, Stephen J Glatt3, Sharon D Chandler1, Todd May1, James Lohr1, Ian P Everall2, William S Kremen1, Ming T Tsuang11Psychiatry, University of California, San Diego, CA, USA; 2Psychiatry, University of Melbourne, Melbourne, Victoria, Australia; 3Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USAAbstract: Identification of genomic biomarkers for neurocognitive performance could ­revolutionize screening, diagnosis, staging, and/or prognosis practices for HIV-associated neurocognitive disorders (HAND). This study sought to explore the relationship between blood-based gene expression and neurocognitive performance. 8 healthy adults were recruited. Subjects were non-smokers, reported taking no medications, and were free of any psychiatric disorders. Correlations adjusting for education and ancestry were conducted to generate lists of genes significantly correlated with scores on neurocognitive test from the National Institute of Mental Health’s Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) consensus cognitive battery (MCCB). Ingenuity pathway analysis was used to identify canonical pathways. For each of the 10 MCCB tests, large effect sizes (r > 0.49) were observed. 65% of the genes and 80% of canonical pathways were unique to 1 of the 10 MCCB tests, albeit none survived a 10% FDR correction. Minimal gene overlap was observed across tests; however, several overlapping canonical pathways were observed. Analysis of the relationship between gene expression alterations and neurocognitive performance may provide the potential for improving our ability to identify genomic markers of HAND as well as provide guidance to physicians and researchers in HIV medicine and other disciplines in their pursuit of viable genomic biomarkers for neurocognitive impairment.Keywords: gene expression, cognitive, methodology, MATRICS

Cognitive deficits are associated with posttraumatic stress disorder (PTSD), but whether such deficits reflect sequelae or risk factors is not fully resolved.To determine, in a representative sample, whether preexposure cognitive ability is associated with risk for PTSD, and whether that risk is genetically mediated.The co-twin-control study involved 2386 male Vietnam-era twin veterans with a mean (SD) age of 41.9 (2.7) years, a population-based sample of men who were in military service during this era. Cognitive ability scores were obtained just before military induction at a mean (SD) age of 19.7 (1.5) years. Participants included only individuals who were exposed to potentially traumatic events and underwent preexposure cognitive testing.Armed Forces Qualification Test (of cognitive ability) percentile scores and PTSD diagnosed by means of structured interviews.We found a significant dose-response relationship between preexposure cognitive ability and risk for PTSD. After controlling for confounders, the highest cognitive ability quartile had a 48% lower risk than the lowest ability quartile (P.001). Non-PTSD-concordant pairs had the highest scores; PTSD-concordant pairs had the lowest scores; and PTSD-discordant pairs had intermediate scores. Differences in Armed Forces Qualification Test scores within twin pairs were significant only in PTSD-discordant pairs (P=.04) and were accounted for specifically by the discordant dizygotic pairs (P=.002). Genetic influences on preexposure cognitive ability explained 5% of the variation in PTSD, but 100% of that relationship was explained by common genes.Preexposure cognitive ability is a risk or a protective factor for PTSD. The variance in PTSD explained by preexposure cognitive ability is accounted for entirely by common genetic factors. Lower cognitive ability may be a marker of less adaptive coping against adverse mental health consequences of exposure to potentially traumatic events. Further study of the potential mechanisms through which cognitive ability confers risk is needed.

Background: Clues to the causes of schizophrenia can be derived from studying first-degree relatives because they are genetically related to an ill family member. Abnormalities observed in nonpsychotic relatives are indicators of possible genetic vulnerability to illness, independent of psychosis. We tested 4 hypotheses: (1) that hippocampal volume is smaller in nonpsychotic relatives than in controls, particularly in the left hemisphere; (2) that hippocampi will be smaller in multiplex relatives as compared with simplex relatives, and both will be smaller than in controls; (3) that hippocampal volumes and verbal declarative memory function will be positively correlated; and (4) that hippocampi will be smaller in patients with schizophrenia than in their nonpsychotic relatives or in controls. Methods: Subjects were 45 nonpsychotic adult firstdegree relatives from families with either 2 people (“multiplex,” n =1 7) or 1 person (“simplex,” n =2 8) diagnosed with schizophrenia, 18 schizophrenic relatives, and 48 normal controls. Sixty contiguous 3-mm coronal, T1-weighted 3-dimensional magnetic resonance images of the brain were acquired on a 1.5-T magnet. Volumes of the total cerebrum and the hippocampus were measured. Results: Compared with controls, relatives, particularly from multiplex families, had significantly smaller left hippocampi. Verbal memory and left hippocampal volumes were significantly and positively correlated. Within families, hippocampal volumes did not differ between schizophrenic patients and their nonpsychotic relatives. Conclusions: Results support the hypothesis that the vulnerability to schizophrenia includes smaller left hippocampi and verbal memory deficits. Findings suggest that smaller left hippocampi and verbal memory deficits are an expression of early neurodevelopmental compromise, reflecting the degree of genetic liability to schizophrenia.

Growing evidence indicates that nonpsychotic relatives of patients with schizophrenia have subtle brain abnormalities in limbic, paralimbic and cortical regions. Verbal memory deficits in adult relatives have also been demonstrated. In this study we present more comprehensive morphometric analyses of the limbic and paralimbic cortices, to test the hypothesis that brain volume reductions, in a distributed memory encoding system, are associated with verbal memory deficits, and that they are more severe in nonpsychotic relatives with two schizophrenic family members (“multiplex”) as compared to one member with the illness (“simplex”). Subjects were 45 nonpsychotic first degree relatives of patients with schizophrenia and 48 matched normal controls. Sixty contiguous 3 millimeter coronal, T1-weighted 3D magnetic resonance images of the entire brain were acquired on a 1.5 Tesla magnet. Cortical and subcortical gray and white matter were segmented using a semi-automated intensity contour mapping algorithm. After segmenting the hippocampus and amygdala as a continuous volume, we parcellated the hippocampus from the amygdala. We used a new method to parcellate the fornix and mamillary bodies, along with the hippocampus, and the parahippocampal gyrus. Findings showed that the relatives had significant volumetric reductions in the left hippocampus, and parahippocampal gyri bilaterally, and that these were more severe in the relatives from “multiplex” families. Verbal memory deficits were significantly associated with hippocampal and parahippocampal volumes in the direction of smaller volumes, worse memory performance. These new data on cognitive and brain endophenotypes provide clues to the pathophysiology of schizophrenia.

Evidence for generalized neuropsychological deficits in schizophrenia is substantial whereas evidence for the specificity of dysfunction is relatively sparse. To assess specificity, we compared neuropsychological function in patients with chronic schizophrenia (n 5 87), patients with chronic psychotic bipolar disorder (n 5 15) and normal controls (n 5 94). An extensive neuropsychological battery was administered. Groups were not significantly different on age, ethnicity and expected intellectual ability (based on single word reading). Patients with schizophrenia and bipolar psychoses were also similar on age at onset, number of hospitalizations, and daily neuroleptic-equivalent dose. Using multivariate analyses of variance with sex and parental SES as covariates, schizophrenia patients were significantly worse than controls on 7 of 8 neuropsychological functions (all but verbal ability), and were significantly more impaired than bipolar patients on abstraction, perceptual-motor speed and vigilance. Bipolar patients were significantly impaired compared to controls on verbal memory. Results were not attenuated when we controlled for a measure of behavior during the testing session, or for IQ, which was significantly lower in patients with schizophrenia. Consistent with previous work, analyses indicated that the two psychiatric groups had similar profile patterns, but that patients with schizophrenia had a more severe impairment than patients with bipolar psychoses. This suggests that level, but not profile type is different between the groups. Further research is required to determine whether similar mechanisms underly the neurocognitive deficits in these disorders.

The existence of separate genetic and environmental forms of schizophrenia has been proposed as the basis for the probable heterogeneity in the etiology of schizophrenia. The rationale for a familial/sporadic strategy that compares positive versus negative family history cases and concordant versus discordant MZ twin pairs is discussed. A review of empirical findings from research utilizing the familial/sporadic strategy is presented. A number of methodological problems that have implications for the application of the strategy and the interpretation of results, such as misclassification, are discussed. It is concluded that the clustering of positive findings in certain domains suggests that this approach holds some promise for elucidating the role of genetic and environmental factors in schizophrenia.

The importance of genetic factors in schizophrenia is clear but the mechanism involved remains obscure. Etiological heterogeneity may be responsible. Recently there has been interest in a putative distinction between genetic and environmental forms of the illness based on a positive or negative family history of the disorder. Those with a positive family history are classified as 'familial' and are considered to be more likely to have the genetic form of the illness. Those with a negative family history are classified as 'sporadic' and considered more likely to have an environmental form of the illness. This paper reports the results of a Monte Carlo simulation study with varying rates of misclassification to determine the statistical power of comparisons between familial and sporadic groups. For a large sample (n = 175) statistical power was moderate to good for effect sizes greater than or equal to 1.0 standard deviation unit and positive predictive value of 0.3 or greater.

Adult romantic attachment styles reflect ways of relating in close relationships and are associated with depression and negative emotionality. We estimated the extent to which dimensions of romantic attachment and negative emotionality share genetic or environmental risk factors in 1,237 middle-aged men in the Vietnam Era Twin Study of Aging (VETSA). A common genetic factor largely explained the covariance between attachment-related anxiety, attachment-related avoidance, depressive symptoms, and two measures of negative emotionality: Stress-Reaction (anxiety), and Alienation. Multivariate results supported genetic and environmental differences in attachment. Attachment-related anxiety and attachment-related avoidance were each influenced by additional genetic factors not shared with other measures; the genetic correlation between the attachment measure-specific genetic factors was 0.41, indicating some, but not complete overlap of genetic factors. Genetically informative longitudinal studies on attachment relationship dimensions can help to illuminate the role of relationship-based risk factors in healthy aging.

Loos, Ruth J F/0000-0002-8532-5087; Fagnani, Corrado/0000-0001-5771-7772; Busjahn, Andreas/0000-0001-9650-6919; Skytthe, Axel E/0000-0002-8629-4913; Craig, Jeffrey M/0000-0003-3979-7849; Knafo-Noam, Ariel/0000-0003-0613-1960; Kandler, Christian/0000-0002-9175-235X; Christensen, Kaare/0000-0002-5429-5292; Kaprio, Jaakko/0000-0002-3716-2455; Kyvik, Kirsten O/0000-0003-2981-0245; Siribaddana, Sisira/0000-0001-5821-2557; Montgomery, Grant W/0000-0002-4140-8139; Ordonana, Juan R./0000-0001-7779-6017; Colodro-Conde, Lucia/0000-0002-9004-364X; Huibregtse, Brooke M./0000-0003-0977-7249; ONCEL, Sevgi YURT/0000-0002-0990-292X; Duncan, Glen/0000-0001-6909-1869; Magnusson, Patrik/0000-0002-7315-7899; Heikkila, Kauko/0000-0002-9256-8028; mangino, massimo/0000-0002-2167-7470; Medland, Sarah E/0000-0003-1382-380X; Aliev, Fazil/0000-0001-8357-4699; Tan, Qihua/0000-0003-3194-0030; ROMERA, JUAN FRANCISCO SANCHEZ/0000-0002-5405-6216; Sund, Reijo/0000-0002-6268-8117; D'Ippolito, Cristina/0000-0001-7902-9380; Haworth, Claire/0000-0002-8608-289X; Tan, Qihua/0000-0003-3194-0030; Bartels, Meike/0000-0002-9667-7555; Aaltonen, Sari/0000-0002-2873-4263; Sodemann, Morten/0000-0001-8992-2500; Rebato, Esther/0000-0003-1221-8501; van Beijsterveldt, Toos/0000-0002-6617-4201; McAdams, Tom/0000-0002-6825-3499; Llewellyn, Clare/0000-0002-0066-2827; Franz, Carol/0000-0002-8987-1755; Boivin, Michel/0000-0001-8621-9844; Hotopf, Matthew/0000-0002-3980-4466; Kremen, William/0000-0002-8629-5609; Plomin, Robert/0000-0002-0756-3629; Harden, Kathryn/0000-0002-1557-6737; Rasmussen, Finn/0000-0001-7915-7809; Willemsen, Gonneke/0000-0003-3755-0236; Derom, Catherine/0000-0001-5574-796X; Pahlen, Shandell/0000-0003-0753-4155; Silventoinen, Karri/0000-0003-1759-3079; Rijsdijk, Fruhling/0000-0003-4762-2803; Saffery, Richard/0000-0002-9510-4181 WOS: 000361660800008 PubMed: 26337138 A trend toward greater body size in dizygotic (DZ) than in monozygotic (MZ) twins has been suggested by some but not all studies, and this difference may also vary by age. We analyzed zygosity differences in mean values and variances of height and body mass index (BMI) among male and female twins from infancy to old age. Data were derived from an international database of 54 twin cohorts participating in the COllaborative project of Development of Anthropometrical measures in Twins (CODATwins), and included 842,951 height and BMI measurements from twins aged 1 to 102 years. The results showed that DZ twins were consistently taller than MZ twins, with differences of up to 2.0 cm in childhood and adolescence and up to 0.9 cm in adulthood. Similarly, a greater mean BMI of up to 0.3 kg/m(2) in childhood and adolescence and up to 0.2 kg/m(2) in adulthood was observed in DZ twins, although the pattern was less consistent. DZ twins presented up to 1.7% greater height and 1.9% greater BMI than MZ twins; these percentage differences were largest in middle and late childhood and decreased with age in both sexes. The variance of height was similar in MZ and DZ twins at most ages. In contrast, the variance of BMI was significantly higher in DZ than in MZ twins, particularly in childhood. In conclusion, DZ twins were generally taller and had greater BMI than MZ twins, but the differences decreased with age in both sexes. National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01 MH58354]; National Institute on AgingUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) [1RO1-AG13662-01A2]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R21 AG039572]; WT Grant Foundation; University of London Central Research fund; Medical Research CouncilMedical Research Council UK (MRC) [G81/343, G120/635]; Economic and Social Research CouncilEconomic & Social Research Council (ESRC) [RES-000-22-2206]; Institute of Social Psychiatry [06/07-11]; Leverhulme Research FellowshipLeverhulme Trust [RF/2/RFG/2008/0145]; Goldsmiths, University of London; National Research Foundation of KoreaNational Research Foundation of Korea [NRF-371-2011-1 B00047]; National Institute of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NIA R01 AG018384, R01 AG018386, R01 AG022381, R01 AG022982]; Cooperative Studies Program of the Office of Research & Development of the US Department of Veterans AffairsUS Department of Veterans Affairs; Centre of Research Excellence from the National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [grant ID 1079102]; Michigan State University; National Institute of Mental Health (NIMH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01]; Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) [R01-HD066040]; MSU Foundation [11-SPG-2518]; California Tobacco-Related Disease Research ProgramUniversity of California System [7RT-0134H, 8RT-0107H, 6RT-0354H]; The National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1R01ESO15150-01, R01 HD068435, R01 MH062375]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81125007]; Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [437015, 607358]; Bonnie Babes Foundation [BBF20704]; Financial Markets Foundation for Children [032-2007]; Victorian Government's Operational Infrastructure Support Program; ENGAGE-European Network for Genetic and Genomic Epidemiology; National Institute of Alcohol Abuse and AlcoholismUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) [AA-12502, AA-00145, AA-09203]; Academy of Finland Center of Excellence in Complex Disease GeneticsAcademy of Finland [213506, 129680]; Academy of FinlandAcademy of Finland [100499, 205585, 118555, 141054, 265240, 263278, 264146]; Osaka University's International Joint Research Promotion Program; Kirikkale University Research Grant: KKUKirikkale University [2009/43]; TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [114C117]; European Research Council (ERC)European Research Council (ERC) [240994]; European Union's Seventh Framework Programme ENGAGE ConsortiumEuropean Union (EU) [HEALTH-F4-2007- 201413]; European Union's Seventh Framework Programme BioSHaRE EUEuropean Union (EU) [HEALTH-F4-2010-261433]; Seneca FoundationFundacion Seneca; Regional Agency for Science and Technology, Murcia, Spain [08633/PHCS/08, 15302/PHCS/10]; Ministry of Science and Innovation, SpainSpanish Government [PSI11560-2009]; UK Medical Research CouncilMedical Research Council UK (MRC) [G0901245]; UK Biotechnology and Biological Sciences Research CouncilBiotechnology and Biological Sciences Research Council (BBSRC) [31/D19086]; Portuguese agency for research (The Foundation for Science and Technology [FCT] [POCI/DES/56834/2004]; Wellcome TrustWellcome Trust; European Community's Seventh Framework ProgrammeEuropean Union (EU); National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London; Netherlands Organization for Scientific Research (NWO)Netherlands Organization for Scientific Research (NWO); MagW/ZonMW [904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192]; VU University's Institute for Health and Care Research (EMGO+); ERCEuropean Research Council (ERC) [ERC-230374]; Avera Institute, Sioux Falls, South Dakota (USA); Cancer Research UKCancer Research UK [C1418/A7974]; Japan Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science [15H05105]; Fonds Quebecois de la Recherche sur la Societe et la CultureFQRNT; Fonds de la Recherche en Sante du QuebecFonds de la Recherche en Sante du Quebec; Social Science and Humanities Research Council of Canada; National Health Research Development Program; Canadian Institutes for Health ResearchCanadian Institutes of Health Research (CIHR); Sainte-Justine Hospital's Research Center; Canada Research Chair ProgramCanada Research Chairs; [FP7-HEALTH-F4-2007]; [201413]; [NIH RC2 HL103416]; Cancer Research UKCancer Research UK [14133]; Medical Research CouncilMedical Research Council UK (MRC) [G0901245, G9817803B]; NNF Center for Basic Metabolic ResearchNovo Nordisk Foundation [Metabolic Genetics]; Novo Nordisk FondenNovo NordiskNovo Nordisk Foundation [NNF10CC1016515] This study was conducted within the CODATwins project (Academy of Finland #266592). Support for participating twin projects: The University of Southern California Twin Study is funded by a grant from the National Institute of Mental Health (R01 MH58354). The Carolina African American Twin Study of Aging (CAATSA) was funded by a grant from the National Institute on Aging (grant 1RO1-AG13662-01A2) to K. E. Whitfield. The NAS-NRC Twin Registry acknowledges financial support from the National Institutes of Health (grant No. R21 AG039572). Waves 1-3 of Genesis 12-19 were funded by the WT Grant Foundation, the University of London Central Research fund, and a Medical Research Council Training Fellowship (G81/343) and Career Development Award (G120/635) to Thalia C. Eley. Wave 4 was supported by grants from the Economic and Social Research Council (RES-000-22-2206) and the Institute of Social Psychiatry (06/07-11) to Alice M. Gregory, who was also supported at that time by a Leverhulme Research Fellowship (RF/2/RFG/2008/0145). Wave 5 was supported by funding to Alice M. Gregory from Goldsmiths, University of London. Anthropometric measurements of the Hungarian twins were supported by Medexpert Ltd., Budapest, Hungary. South Korea Twin Registry is supported by National Research Foundation of Korea (NRF-371-2011-1 B00047). Danish Twin Registry is supported by the National Program for Research Infrastructure 2007 from the Danish Agency for Science, Technology and Innovation, The Research Council for Health and Disease, the Velux Foundation, and the US National Institute of Health (P01 AG08761). Since its origin, the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium). Korean Twin-Family Register was supported by the Global Research Network Program of the National Research Foundation (NRF 2011-220-E00006). Colorado Twin Registry is funded by NIDA center grant DA011015, and Longitudinal Twin Study HD10333. Author Brooke M. Huibregtse is supported by 5T32DA017637-10. Vietnam Era Twin Study of Aging was supported by National Institute of Health grants NIA R01 AG018384, R01 AG018386, R01 AG022381, and R01 AG022982, and, in part, with resources of the VA San Diego Center of Excellence for Stress and Mental Health. The Cooperative Studies Program of the Office of Research & Development of the US Department of Veterans Affairs has provided financial support for the development and maintenance of the Vietnam Era Twin (VET) Registry. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of NIA/NIH, or VA. The Australian Twin Registry is supported by the Centre of Research Excellence (grant ID 1079102) from the National Health and Medical Research Council administered by the University of Melbourne. The Michigan State University Twin Registry has been supported by Michigan State University as well as grants R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, and R03-MH63851-01 from the National Institute of Mental Health (NIMH), R01-HD066040 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD), and 11-SPG-2518 from the MSU Foundation. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of NIMH, NICHD, or the National Institutes of Health.; California Twin Program was supported by The California Tobacco-Related Disease Research Program (7RT-0134H, 8RT-0107H, and 6RT-0354H) and the National Institutes of Health (1R01ESO15150-01). Guangzhou Twin Eye Study is supported by National Natural Science Foundation of China (grant #81125007). PETS was supported by grants from the Australian National Health and Medical Research Council (grant Nos. 437015 and 607358 to Jeffrey M Craig, and Richard Saffery), the Bonnie Babes Foundation (grant No. BBF20704 to Jeffrey M. Craig), the Financial Markets Foundation for Children (grant No. 032-2007 to Jeffrey M. Craig), and by the Victorian Government's Operational Infrastructure Support Program. Data collection and analyses in Finnish twin cohorts have been supported by ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement No. 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to R J Rose, the Academy of Finland Center of Excellence in Complex Disease Genetics (grant Nos. 213506 and 129680), and the Academy of Finland (grants 100499, 205585, 118555, 141054, 265240, 263278, and 264146 to J Kaprio). K Silventoinen is supported by Osaka University's International Joint Research Promotion Program. S.Y. Oncel and F. Aliev are supported by Kirikkale University Research Grant: KKU, 2009/43 and TUBITAK grant 114C117. Longitudinal Israeli Study of Twins was funded by the Starting grant No. 240994 from the European Research Council (ERC) to Ariel Knafo. Data collection and research stemming from the Norwegian Twin Registry is supported, in part, by the European Union's Seventh Framework Programmes ENGAGE Consortium (grant agreement HEALTH-F4-2007- 201413, and BioSHaRE EU (grant agreement HEALTH-F4-2010-261433). The Murcia Twin Registry is supported by the Seneca Foundation, Regional Agency for Science and Technology, Murcia, Spain (08633/PHCS/08 and 15302/PHCS/10) and Ministry of Science and Innovation, Spain (PSI11560-2009). The Twins Early Development Study (TEDS) is supported by a program grant (G0901245) from the UK Medical Research Council, and the work on obesity in TEDS is supported, in part, by a grant from the UK Biotechnology and Biological Sciences Research Council (31/D19086). Madeira data comes from the following project: Genetic and environmental influences on physical activity, fitness and health: the Madeira family study project reference: POCI/DES/56834/2004 founded by the Portuguese agency for research (The Foundation for Science and Technology [FCT]). The Boston University Twin Project is funded by grants (Nos. R01 HD068435 and R01 MH062375) from the National Institutes of Health to K. Saudino. TwinsUK was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. University of Washington Twin Registry was supported by the grant NIH RC2 HL103416 (D. Buchwald, PI).; Netherlands Twin Register acknowledges the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants 904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192, VU University's Institute for Health and Care Research (EMGO+), the ERC (ERC-230374), and the Avera Institute, Sioux Falls, South Dakota (USA). Gemini was supported by a grant from Cancer Research UK (C1418/A7974). The West Japan Twins and Higher Order Multiple Births Registry was supported by Grant-in-Aid for Scientific Research (B) (grant No. 15H05105) from the Japan Society for the Promotion of Science. The Quebec Newborn Twin Study acknowledges financial support from the Fonds Quebecois de la Recherche sur la Societe et la Culture, the Fonds de la Recherche en Sante du Quebec, the Social Science and Humanities Research Council of Canada, the National Health Research Development Program, the Canadian Institutes for Health Research, Sainte-Justine Hospital's Research Center, and the Canada Research Chair Program (Michel Boivin).

Magnusson, Patrik/0000-0002-7315-7899; Christensen, Kaare/0000-0002-5429-5292; Montgomery, Grant W/0000-0002-4140-8139; Fagnani, Corrado/0000-0001-5771-7772; ROMERA, JUAN FRANCISCO SANCHEZ/0000-0002-5405-6216; Siribaddana, Sisira/0000-0001-5821-2557; Tan, Qihua/0000-0003-3194-0030; Busjahn, Andreas/0000-0001-9650-6919; Tan, Qihua/0000-0003-3194-0030; Ordonana, Juan R./0000-0001-7779-6017; Sund, Reijo/0000-0002-6268-8117; Hjelmborg, Jacob/0000-0001-9630-9149; ONCEL, Sevgi YURT/0000-0002-0990-292X; Colodro-Conde, Lucia/0000-0002-9004-364X; Kandler, Christian/0000-0002-9175-235X; McAdams, Tom/0000-0002-6825-3499; mangino, massimo/0000-0002-2167-7470; Huibregtse, Brooke M./0000-0003-0977-7249; Aliev, Fazil/0000-0001-8357-4699; Kaprio, Jaakko/0000-0002-3716-2455; Skytthe, Axel E/0000-0002-8629-4913; Loos, Ruth J F/0000-0002-8532-5087; Pietilainen, Kirsi/0000-0002-8522-1288; Aaltonen, Sari/0000-0002-2873-4263; Pahlen, Shandell/0000-0003-0753-4155; Rasmussen, Finn/0000-0001-7915-7809; van Beijsterveldt, Toos/0000-0002-6617-4201; Franz, Carol/0000-0002-8987-1755; Bartels, Meike/0000-0002-9667-7555; Kyvik, Kirsten Ohm/0000-0003-2981-0245; Willemsen, Gonneke/0000-0003-3755-0236; Pedersen, Nancy/0000-0001-8057-3543; Silventoinen, Karri/0000-0003-1759-3079 WOS: 000406672300007 PubMed: 28679550 Background: Genes and the environment contribute to variation in adult body mass index [BMI (in kg/m(2))], but factors modifying these variance components are poorly understood. Objective: We analyzed genetic and environmental variation in BMI between men and women from young adulthood to old age from the 1940s to the 2000s and between cultural-geographic regions representing high (North America and Australia), moderate (Europe), and low (East Asia) prevalence of obesity. Design: We used genetic structural equation modeling to analyze BMI in twins >= 20 y of age from 40 cohorts representing 20 countries (140,379 complete twin pairs). Results: The heritability of BMI decreased from 0.77 (95% CI: 0.77, 0.78) and 0.75 (95% CI: 0.74, 0.75) in men and women 2029 y of age to 0.57 (95% CI: 0.54, 0.60) and 0.59 (95% CI: 0.53, 0.65) in men 70-79 y of age and women 80 y of age, respectively. The relative influence of unique environmental factors correspondingly increased. Differences in the sets of genes affecting BMI in men and women increased from 20-29 to 60-69 y of age. Mean BMI and variances in BMI increased from the 1940s to the 2000s and were greatest in North America and Australia, followed by Europe and East Asia. However, heritability estimates were largely similar over measurement years and between regions. There was no evidence of environmental factors shared by co-twins affecting BMI. Conclusions: The heritability of BMI decreased and differences in the sets of genes affecting BMI in men and women increased from young adulthood to old age. The heritability of BMI was largely similar between cultural-geographic regions and measurement years, despite large differences in mean BMI and variances in BMI. Our results show a strong influence of genetic factors on BMI, especially in early adulthood, regardless of the obesity level in the population. Medical Research CouncilMedical Research Council UK (MRC) [G120/635]; NIA NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) [P30 AG017265, R01 AG018384]; NIDA NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Drug Abuse (NIDA) [T32 DA017637]; NIDDK NIH HHSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [P30 DK020541]

The search for indicators of vulnerability has been important in schizophrenia research, but, as in many areas, progress has been impeded due to the heterogeneity of schizophrenic disorders. How one conceptualizes the observed heterogeneity is dependent upon the particular genetic model to which one subscribes. In this article, we delineate several models that may account for the distributions of vulnerability indicators in groups of schizophrenic patients and their ill and well relatives. We present these models for heuristic purposes so that they may serve to guide the interpretation of data with respect to the issue of teasing apart familial and nonfamilial environmental components of putative vulnerability indicators. It is suggested that investigators will profit by: a) efforts to combine psychiatric genetic paradigms in order to maximize the yield of family study data, and b) thinking in terms of comparing the ability of different models to account for research findings.