Joanne M. Meyer

Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels

New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D—in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1—and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.

Genetic influences on DSM‐III‐R drug abuse and dependence: A study of 3,372 twin pairs

Research and clinical experience indicate that drug use disorders tend to run in families. The objective of this study was to distinguish between the family environment and genetic factors as the source of this observed family resemblance. Data were collected by telephone interview from members of the Vietnam Era Twin Registry, comprising male twin pairs who served in the U.S. military between 1965 and 1975. There were 3,372 pairs in which both twins participated. Drug use disorder was defined as receiving a diagnosis of drug abuse or dependence according to DSM-III-R; 10.1% of the sample had abused or been dependent on at least one illicit drug. A significant difference between concordance rates for monozygotic (26.2%) vs. dizygotic (16.5%) twins indicated a genetic influence on drug use disorder. Biometrical modeling indicated that genetic factors (34% of the variance), the environment shared by twins (28% of the variance), and the nonshared environment (38% of the variance) had significant influences of similar magnitudes on the individuals risk of developing a drug use disorder. These results support the application of molecular genetic approaches to elucidate the genetic influence on drug use disorder, as well as the potential efficacy of environmental intervention to reduce risk.

Integrating nature and nurture: Implications of person-environment correlations and interactions for developmental psychopathology

The developmental interplay between nature and nurture is discussed, with particular reference to implications for research in developmental psychopathology. The general principles include individual differences in reactivity to the environment, two-way interplay between intraindividual biology and environmental influences, and the need to consider broader social contextual features. Individuals actively process their experiences; they also act on their environment to shape and select their experiences, and individual characteristics change over time. Key findings on genetic effects include their ubiquitous influence, the multifactorial origin of most psychopathology, the involvement of several genes in most mental disorders, some genetic effects operate through dimensional risk features rather than directly on disorder, some genetic effects are dependent on gene-environment correlations and interactions, and genetic effects increase with age. Key findings on environmental effects include their ubiquitous influence, the genetic mediation of some supposed environmental effects, the importance of passive gene-environment correlations, the paucity of evidence regarding environmental effects on lifetime liability to psychopathology, the lack of understanding of environmental effects on the organism, and the importance of nonshared environmental effects. Research strategies to investigate environmental risk mediation include the range of genetically sensitive designs, migration studies, secular trend investigations, studies of nonfamilial environments, and examination of intraindividual change in relation to measured environmental alterations. Proximal processes involved in person-environment interplay are discussed in relation to person-environment interactions and evocative and active person-environment correlations.

NIMH genetics initiative millennium schizophrenia consortium: Linkage analysis of African-American pedigrees

The NIMH Genetics Initiative is a multi-site collaborative study designed to create a national resource for genetic studies of complex neuropsychiatric disorders. Schizophrenia pedigrees have been collected at three sites: Washington University, Columbia University, and Harvard University. This article-one in a series that describes the results of a genome-wide scan with 459 short-tandem repeat (STR) markers for susceptibility loci in the NIMH Genetics Initiative schizophrenia sample-presents results for African-American pedigrees. The African-American sample comprises 30 nuclear families and 98 subjects. Seventy-nine of the family members were considered affected by virtue of having received a DSMIII-R diagnosis of schizophrenia (n = 71) or schizoaffective disorder, depressed (n = 8). The families contained a total of 42 independent sib pairs. While no region demonstrated evidence of significant linkage using the criteria suggested by Lander and Kruglyak, several regions, including chromosomes 6q16-6q24, 8pter-8q12, 9q32-9q34, and 15p13-15q12, showed evidence consistent with linkage (P = 0.01-0.05), providing independent support of findings reported in other studies. Moreover, the fact that different genetic loci were identified in this and in the European-American samples, lends credence to the notion that these genetic differences together with differences in environmental exposures may contribute to the reported differences in disease prevalence, severity, comorbidity, and course that has been observed in different racial groups in the United States and elsewhere.

Genome scan of European-American Schizophrenia pedigrees : Results of the NIMH Genetics Initiative and Millennium Consortium

The Genetics Initiative of the National Institute of Mental Health (NIMH) was a multisite study that created a national repository of DNA from families informative for genetic linkage studies of schizophrenia, bipolar disorder, and Alzheimers disease. The schizophrenia families were collected by three sites: Washington University, Harvard University, and Columbia University. This article, one in a series that describes the data collected for linkage analysis by the schizophrenia consortium, presents the results for the European-American sample. The European-American sample comprised 43 nuclear families and 146 subjects. Ninety-six of the family members were considered affected by virtue of having received a DSM-III-R diagnosis of schizophrenia (N = 82) or schizoaffective disorder, depressed (N = 14). The families contained a total of 50 independent sib-pairs. Using the significance threshold criteria suggested by Lander and Kruglyak [(1995): Nat Genet 241-247], no region showed statistically significant evidence for linkage; two markers on chromosome 10p showed statistical evidence suggestive of linkage using the criteria of Lander and Kruglyak [(1995): Nat Genet 241-247]: D10S1423 (nonparametric linkage (NPL) Z = 3.4, P = .0004) and its neighbor, D10S582 (NPL Z = 3.2, P = .0006).

Assortative mating for major psychiatric diagnoses in two population-based samples

BACKGROUND Previous studies on assortment for psychiatric disorders have reported discrepant findings. We aimed to test whether there is a significant association for psychiatric diagnoses, including alcoholism, generalized anxiety disorder, major depressive disorder, panic disorder and phobias between husbands and wives in two population-based samples. We further evaluated whether marital resemblance occurs primarily within or across psychiatric disorders and if assortment for psychopathology is primary or secondary to assortment for correlated variables. METHODS A model for mate selection addressed whether the correlation between mates for psychiatric disorders arises from direct assortment (primary homogamy) or through correlation with other variables for which assortment occurs (secondary homogamy) or through cross-variable assortment. The model accounted for within-person co-morbidity as well as across-spouse data. RESULTS Findings suggested that a moderate degree of assortment exists both within and across psychiatric diagnoses. Only a small amount of the observed marital resemblance for mental illness could be explained by assortment for correlated variables such as age, religious attendance and education. Similar results were obtained for the two samples separately and confirmed in their joint analysis, revealing that the co-morbidity and assortment findings, except for the marital correlation for age, religious attendance and education, replicate across samples. CONCLUSIONS Significant but moderate primary assortment exists for psychiatric disorders. The bias in twin studies that have ignored the small amount of assortment is negligible.

Genetic contribution to risk of smoking initiation: Comparisons across birth cohorts and across cultures

Self-report data on smoking initiation (whether the respondent admitted ever having smoked) were obtained from three large adult twin samples (Australia, N = 3,808 pairs; Virginia, N = 2,145 pairs; AARP, N = 3,620 pairs). Data were broken down into birth cohorts, and genetic models were fitted to test whether the decline, in more recent birth cohorts, in the percentage of individuals becoming smokers has led to a change in the relative contributions of genes and environment to risk of becoming a smoker. Despite a marked change in the proportion of male respondents who reported ever having smoked, we found no evidence for cohort differences in genetic and environmental effects (no Genotype x Cohort interaction). Significant differences in genetic and environmental parameters were found between sexes, and between the Australian and the two U.S. samples. In the U.S. samples, estimates of the genetic contribution to risk of becoming a smoker were 60% in men, 51% in women. In the Australian sample, heritability estimates were 33% in men, but 67% in women. Significant shared environmental effects on smoking initiation also were found, accounting for 23% of the variance in U.S. men, 28% of the variance in U.S. women, 39% of the variance in Australian men, and 15% of the variance in Australian women. In models that allowed for the environmental impact of cotwin smoking on a twins risk of smoking initiation, estimates of the direct genetic contribution to risk of smoking initiation were comparable or higher (49-58% in U.S. women and 71% in Australian women; 58-61% in U.S. men, and 37% in Australian men).

Locating human quantitative trait loci: Guidelines for the selection of sibling pairs for genotyping

Simulation studies were conducted to assess the relative merits of different nonrandom sampling strategies for the selection of sibling pairs for genotyping in the attempt to locate individual loci (QTLs) contributing to variation in human quantitative traits. For a constant amount of variation contributed by a QTL (25% of the total) the frequencies and dominance relationships of a trait increasing allele were varied. Three strategies for selection of pairs for genotyping were based on the phenotypic values of the siblings: “Concordant sib pairs” (CSP) are pairs in which both individuals exceed a given threshold value; “discordant sib pairs” (DSP) are pairs in which one member exceeds a given upper threshold and the other is below a specified lower threshold; and “most similar pairs” (MSP) are pairs selected for falling below a specified percentile ranking of the within-pair mean square for the quantitative trait. Tests for linkage with markers at 1, 2, 5, 10, and 20 cM from each of the QTLs were conducted for each of the selected samples and compared with tests based on the regression, in the entire sample, of within pair variation on the proportion of alleles identical by descent (IBD) at each marker locus. Tests for the effect of the increasing allele at the QTL (“candidate gene”) were also conducted for the DSP pairs. No single nonrandom selection procedure yields as much as half the information realized in the total sample. However, a combined strategy which involves genotyping the 5% of MSP and DSP for the upper and lower quintiles of values of the quantitative trait (a further 3% of the sample approximately) yields lod scores which are usually more than 65% of the values realized for the entire sample. Tests comparing the proportion of increasing alleles in high- and low-scoring siblings from DSP samples are uniformly very powerful for detecting candidate loci. Even when it is not possible to measure the entire range of the phenotype with uniform precision, some attempt to differentiate among individuals in a common “unaffected” class of individuals can lead to considerable increase in power.

A Model System for Analysis of Family Resemblance in Extended Kinships of Twins

The “Virginia 30,000” comprise 29,698 subjects from the extended kinships of 5670 twin pairs. Over 80 unique correlations between relatives can be derived from these kinships, comprised of monozygotic (MZ) and dizygotic (DZ) twins and their spouses, parents, siblings, and children. This paper describes the first application of a fairly general model for family resemblance to data from the Virginia 30,000. The model assesses the contributions of additive and dominant genetic effects in the presence of vertical cultural inheritance, phenotypic assortative mating, shared twin and sibling environments, and within-family environment. The genetic and environmental effects can be dependent on sex. Assortment and cultural inheritance may be based either on the phenotype as measured or on a latent trait of which the measured phenotype is an unreliable index. The model was applied to church attendance data from this study. The results show that the contributions of genes, vertical cultural inheritance, and genotype-environment covariance are all important, but their contributions are significantly heterogeneous over sexes. Phenotypic assortative mating has a major impact on family resemblance in church attendance.

Familial determinants of moderate and intense physical activity : a twin study

This twin study estimates familial clustering of moderate and intense leisure-time physical activity and investigates quantitatively its genetic and environmental components. Study subjects are 3,344 male twin pairs aged 33-51 yr. Moderate activity levels were assessed with six questions about discretionary walking or stair climbing for exercise. Five questions assessed regular participation in specific, intense athletic activities (running, bicycling, swimming, racquet, and other sports). Familial aggregation is estimated by odds ratio of one twin engaging in an activity when his co-twin does. Monozygotic and dizygotic twin correlations were compared to estimate genetic and nongenetic sources of phenotypic variation. For each activity, the familial aggregation odds ratio was statistically significant with values between 2.9 to 4.6 for intense activities and between 1.4 to 1.9 for all moderate activities but one. Monozygotic twin correlations were higher than dizygotic, suggesting genes play a role in the observed phenotypic variation. For four questions, and a compromise scale of moderate activity, the difference between correlations was statistically significant (P < 0.05). In this cohort, much of the phenotypic variability for both moderate and intense activities is a result of familial effects. Genes may influence regular participation in specific intense exercises more than moderate activity, such as walking for exercise.