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Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA2) activity have been shown to be associated with increased risk of coronary heart disease and an inhibitor of this enzyme is under development for the treatment of that condition. A Val279Phe null allele in this gene, that may influence patient eligibility for treatment, is relatively common in East Asians but has not been observed in Europeans. We investigated the existence and functional effects of low frequency alleles in a Western European population by re-sequencing the exons of PLA2G7 in 2000 samples. In all, 19 non-synonymous single-nucleotide polymorphisms (nsSNPs) were found, 14 in fewer than four subjects (minor allele frequency

Genome-wide association studies succeeded in finding genetic variants associated with various phenotypes, but a large portion of the predicted genetic contribution to many traits remains unknown. One plausible explanation is that some missing variation is due to rare variants. Latest sequencing technology facilitates the investigation of such rare variants, but their statistical analysis remains challenging. For quantitative traits, a commonly used approach is to contrast the frequency of putatively functional rare variants between subjects in the two tails of the trait distribution. The contrast is usually performed by Fisher's exact or similar test. These tests are conservative as they discard trait rank information and are most useful under the unrealistic homogeneity assumption (i.e., variants have similar effects). We propose, and investigate via simulations, various designs for resequencing studies and statistical methods that incorporate information about rank, predicted function and allow for heterogeneity of effects. We propose designs which accommodate heterogeneity by sequencing both tails and the middle of the trait and novel statistical tests for trend, for heterogeneity and for a combination of the two. The conclusions of the simulations are four fold: (1) sequencing both tails and the middle of the trait distributions is desirable when heterogeneity is suspected, (2) trend and heterogeneity statistics should be used alongside other methods, (3) using rank information improves power over Fisher's exact test when the number of rare variants is not very large and (4) due to high misclassification rates, incorporating current predictions of a variant's function does not improve power. Genet. Epidemiol. 35: 226-235, 2011. © 2011 Wiley-Liss, Inc.

Published data support genetic variants, as well as certain infectious agents, as potential risk factors for schizophrenia. Less is known about interactions between the risk factors.To evaluate exposure to infectious agents and host genetic variation as joint risk factors.We investigated four infectious agents: cytomegalovirus (CMV), herpes simplex viruses 1 and 2 (HSV1, HSV2), and Toxoplasma gondii (TOX). We initially compared exposure using specific serum antibodies, among simplex and multiplex nuclear families (one or more than one affected offspring, respectively). If interactions between infectious agents and host genetic variation are important risk factors for schizophrenia, we reasoned that they would be more prominent among multiplex versus simplex families. We also evaluated the role of variation at chromosome 6p21-p23 in conjunction with exposure. We used 22 short tandem repeat polymorphisms (STRPs) dispersed across this region.Though exposure to all four agents was increased among multiplex families versus simplex families, the difference was consistently significant only for CMV (odds of exposure to CMV in multiplex families: 2.47, 95% CI: 1.48-5.33). Transmission disequilibrium tests and case-control comparisons using STRPs revealed significant linkage/association with D6S2672 among CMV+ schizophrenia patients.Polymorphisms near D6S2672 could confer risk for schizophrenia in conjunction with CMV exposure.

Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.

Many candidate gene association studies have evaluated incomplete, unrepresentative sets of single nucleotide polymorphisms (SNPs), producing non-significant results that are difficult to interpret. Using a rapid, efficient strategy designed to investigate all common SNPs, we tested associations between schizophrenia and two positional candidate genes: ACSL6 (Acyl-Coenzyme A synthetase long-chain family member 6) and SIRT5 (silent mating type information regulation 2 homologue 5). We initially evaluated the utility of DNA sequencing traces to estimate SNP allele frequencies in pooled DNA samples. The mean variances for the DNA sequencing estimates were acceptable and were comparable to other published methods (mean variance: 0.0008, range 0-0.0119). Using pooled DNA samples from cases with schizophrenia/schizoaffective disorder (Diagnostic and Statistical Manual of Mental Disorders edition IV criteria) and controls (n=200, each group), we next sequenced all exons, introns and flanking upstream/downstream sequences for ACSL6 and SIRT5. Among 69 identified SNPs, case-control allele frequency comparisons revealed nine suggestive associations (P

Multipoint linkage methods are powerful tools that are often employed as the first means to discover alleles affecting liability to diseases. With the advent of dense marker maps, linkage disequilibrium (LD) between markers is inevitable and it comes at the cost of bias and an increased rate of false-positive findings for linkage analyses that assume alleles of different markers are independent. I propose a "multipoint on subsets" method that avoids this issue by partitioning the markers into interlaced and non-overlapping subsets. Each subset is analyzed separately, their statistics are then averaged, and the resulting average is standardized by its estimated standard deviation. In addition to being robust to the challenges induced by dependent marker alleles, data simulated under linkage equilibrium show that the proposed method does not suffer any detectable loss of power when compared to traditional methods.

Psychotic symptoms in subjects with Alzheimer disease (AD with psychosis, AD+P) define a phenotype characterized by greater cognitive burden than in AD without psychosis. We have proposed that genes of small effect may contribute to the risk for expression of psychosis in multiple disorders, including AD. Recently, sex-differential association of a three-locus haplotype, including a G → A transition at codon 108/158 of catechol-O-methyltransferase (COMT) resulting in a Val → Met substitution, has been reported to confer an increased risk for schizophrenia. The main objective of the study was to determine if COMT genetic variation is associated with risk of psychosis in AD, and included a case–control study of 373 individuals diagnosed with AD with, or without, psychosis. All subjects were characterized for alleles at the three loci associated with schizophrenia, RS737865, COMT G → A 108/158 (RS4680), and RS165599, and for a C/T transition adjacent to an estrogen response element (ERE6) in the COMT P2 promoter region. Both single locus and haplotype tests of association were conducted. Logit models were used to examine independent and interacting effects of alleles at the associated loci. All analyses were stratified by sex. In female subjects, RS4680 demonstrated a modest association with AD+P; RS737865 demonstrated a trend towards an association. There was a highly significant association of AD+P with the four-locus haplotype, which resulted from additive effects of alleles at RS4680 and ERE6 (or RS737865, as this locus was in almost absolute linkage disequilibrium (LD) with ERE6). In male subjects, no single locus test was significant, but there remained a strong association between AD+P and the four-locus haplotype. This association appeared to result from interaction of the ERE6/RS737865, RS4680, and RS165599 loci. Genetic variation in COMT is associated with AD+P, and thus appears to contribute to psychosis risk across disorders. Sex-differential associations of COMT with psychosis may result from variation at, or in LD with, ERE6. Examination of variation at ERE6 in subjects with schizophrenia, and further examination of the independent and additive effects of variations in COMT on gene expression, is warranted.

The authors have previously demonstrated familial clustering of psychotic symptoms in late-onset Alzheimer disease (LOAD+P) and sought to estimate and explore the nature of the heritability of LOAD+P.The heritability of LOAD+P, defined by single and multiple psychotic symptoms, was estimated with data from the National Institute of Mental Health AD Genetics Initiative.The estimated heritability for LOAD+P defined by multiple psychotic symptoms was 61%; for LOAD+P defined by any occurrence of psychotic symptoms, it was 30%.Multiplicity of symptoms may represent a useful means for defining a genetically determined LOAD+P phenotype.

To investigate whether the dopaminergic system plays a role in the etiology of anorexia nervosa (AN) via the dopamine D2 receptor, we investigated association and transmission disequilibrium at seven single-nucleotide polymorphisms (SNPs) spanning about 75 kbp of the gene DRD2. We studied 191 probands with a DSM-IV diagnosis of AN, 457 parents and affected relatives with a DSM-IV eating disorder diagnosis, and 98 unrelated, female, normal weight controls. The -141 C/- insertion/deletion (-141 Indel), previously shown to affect DRD2 transcription efficiency, and multiple exon seven polymorphisms, one of which has previously been shown to affect DRD2 transcript stability, exhibited statistically significant association with diagnosis in haplotype transmission disequilibrium and in haplotype case : control analyses. Significant linkage disequilibrium between the -141 Indel and two exon seven SNPs (939Y and 957Y) was observed over a distance of >50 kbp in the AN probands but not in the controls. Genetically transmitted variation in D2 dopamine receptor expression mediated by functional polymorphisms affecting transcription and translation efficiency may play a role in vulnerability to AN.

PUBLISHED, Several independent studies and meta-analyses aimed at identifying genomic regions linked to bipolar disorder (BP) have failed to find clear and consistent evidence of linkage regions. Our hypothesis is that combining the original genotype data provides benefits of increased power and control over sources of heterogeneity that outweigh the difficulty and potential pitfalls of the implementation. We conducted a combined analysis using the original genotype data from 11 BP genomewide linkage scans comprising 5,179 individuals from 1,067 families. Heterogeneity among studies was minimized in our analyses by using uniform methods of analysis and a common, standardized marker map and was assessed using novel methods developed for meta-analysis of genome scans. To date, this collaboration is the largest and most comprehensive analysis of linkage samples involving a psychiatric disorder. We demonstrate that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease. Our results establish genomewide significant linkage to BP on chromosomes 6q and 8q, which provides solid information to guide future gene-finding efforts that rely on fine-mapping and association approaches.

Twin and family studies suggest that genetic variants contribute to the pathogenesis of bulimia nervosa (BN) and anorexia nervosa (AN). The Price Foundation has supported an international, multisite study of families with these disorders to identify these genetic variations. The current study presents the clinical characteristics of this sample as well as a description of the study methodology.All probands met modified criteria for BN or bulimia nervosa with a history of AN (BAN) as defined in the 4th ed. of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 1994). All affected relatives met DSM-IV criteria for BN, AN, BAN, or eating disorders not otherwise specified (EDNOS). Probands and affected relatives were assessed diagnostically using both trained-rater and self-report assessments. DNA samples were collected from probands, affected relatives, and available biologic parents.Assessments were obtained from 163 BN probands and 165 BAN probands. Overall, there were 365 relative pairs available for linkage analysis. Of the affected relatives of BN probands, 62 were diagnosed as BN (34.8%), 49 as BAN (27.5%), 35 as AN (19.7%), and 32 as EDNOS (18.0%). For the relatives of BAN probands, 42 were diagnosed as BN (22.5%), 67 as BAN (35.8%), 48 as AN (25.7%), and 30 as EDNOS (16.0%).This study represents the largest genetic study of eating disorders to date. Clinical data indicate that although there are a large number of individuals with BN disorders, a range of eating pathology is represented in the sample, allowing for the examination of several different phenotypes in molecular genetic analyses.

Objective This study compares personality variables of men with eating disorders to women with eating disorders. Method Data were obtained from an international study of the genetics of eating disorders. Forty-two male participants were age-band matched at 1:2 ratio to females from the same study. Personality features were compared between males and females controlling for diagnostic subgroup. Results Males with eating disorders appear to be slightly less at risk for perfectionism, harm avoidance, reward dependence, and cooperativeness than females. Few differences were found when diagnostic subgroup was considered. Conclusion Observed differences in personality variables may help explain the difference in incidence and prevalence of eating disorders in men and women.

Psychotic symptoms in Alzheimer disease (AD) identify a phenotype with distinct neurobiology and genetic architecture. The authors investigated whether AD with psychosis is homogeneous or is a composite of subtypes.Authors performed factor and cluster analyses of the psychotic-symptom items of the CERAD Behavioral Rating Scale in 188 probable and possible AD subjects who have displayed at least one psychotic symptom.Exploratory factor analysis resulted in a one-factor solution that comprised misidentification delusions, auditory and visual hallucinations, and the misidentification of people. Persecutory delusions were also frequently present and were independent of the misidentification/hallucination factor. Cluster analysis yielded similar results.Misidentification/hallucinations and persecutory delusions may identify two subtypes of psychosis in AD. Longitudinal study is needed to determine whether these proposed subtypes remain stable and independent over time or merge into a single group over the course of illness.

Bulimia nervosa (BN) is strongly familial, and additive genetic effects appear to contribute substantially to the observed familiality. In turn, behavioral components of BN, such as self-induced vomiting, are reliably measured and heritable. To identify regions of the genome harboring genetic variants conferring susceptibility to BN, we conducted a linkage analysis of multiplex families with eating disorders that were identified through a proband with BN. Linkage analysis of the entire sample of 308 families yielded a double peak, with the highest nonparametric multipoint maximum LOD score (MLS), of 2.92, on chromosome 10. Given the high heritability of self-induced vomiting and the reliability with which it can be measured, we performed linkage analysis in a subset (n=133) of families in which at least two affected relatives reported a symptom pattern that included self-induced vomiting. The highest MLS (3.39) observed was on chromosome 10, between markers D10S1430 and D10S1423. These results provide evidence of the presence of a susceptibility locus for BN on chromosome 10p. Using simulations, we demonstrate that both of these scores, 2.92 and 3.39, meet the widely accepted criterion for genomewide significance. Another region on 14q meets the criterion for genomewide suggestive linkage, with MLSs of 1.97 (full sample) and 1.75 (subset) at 62 centimorgans from p-ter.

Nephrotoxicity is an adverse effect of cyclosporine and tacrolimus. Studies comparing their long-term nephrotoxicities are lacking. This study evaluates the nephrotoxicity of these agents over a 7-year period following heart transplantation. Pediatric heart-transplant recipients receiving cyclosporine or tacrolimus as primary immunosuppression were evaluated at two centers from 1982 to 1998. Data collected included serum creatinine, height and weight prior to transplantation, at 1 and 6 months and 1 years post transplantation, and at yearly intervals thereafter. Creatinine clearance was calculated and compared between the two groups. Glomerular filtration rate was measured using Tc-99m diethylenetriaminepentacetic acid. In total, 123 patients were evaluated. Demographic data of the two groups were comparable. Creatinine clearance demonstrated a steady decline. This decline did not differ statistically between the two groups: tacrolimus 98.9 and 90.7mL/min/1.73 m2 at 1 month and 5 years, respectively; cyclosporine 110.7 and 81.7 mL/min/ 1.73 m2 at 1 month and 5 years, respectively. Four patients developed end-stage renal failure. Calculated creatinine clearance consistently overestimated glomerular filtration rate, the latter being greater than 2 standard deviations below the mean normal in 38% of patients. We conclude that the nephrotoxicities of tacrolimus and cyclosporine are comparable over the medium- to long-term in pediatric heart-transplant recipients.

Although a portion of risk for late-onset AD (LOAD) is attributable to APOE, the search for other loci is ongoing. The authors hypothesize that psychotic symptoms with LOAD (LOAD+P) identify a potentially more etiologically homogeneous form of AD. Linkage analysis of families with LOAD+P identified one significant and several suggestive novel linkage signals, which bolsters the conjecture of greater etiologic homogeneity.

Association between disease and genetic polymorphisms often contributes critical information in our search for the genetic components of common diseases. Devlin and Roeder [1999: Biometrics 55:997-1004] introduced genomic control, a statistical method that overcomes a drawback to the use of population-based samples for tests of association, namely spurious associations induced by population structure. In essence, genomic control (GC) uses markers throughout the genome to adjust for any inflation in test statistics due to substructure. To date, genomic control (GC) has been developed for binary traits and bi- or multiallelic markers. Tests of association using GC have been limited to single genes. In this report, we generalize GC to quantitative traits (QT) and multilocus models. Using statistical analysis and simulations, we show that GC controls spurious associations in reasonable settings of population substructure for QT models, including gene-gene interaction. Through simulations, we explore GC power for both random and selected samples, assuming the QT locus tested is causal and its specific heritability is 2.5-5%. We find that GC, combined with either random or selected samples, has good power in this setting, and that more complex models induce smaller GC corrections. The latter suggests greater power can be achieved by specifying more complex genetic models, but this observation only follows when such models are largely correct and specified a priori.

Background. An international, multi-site study funded by the Price Foundation has collected 237 affected relative pairs to identify potential genetic factors that may contribute to the pathogenesis of anorexia nervosa (AN). The current report utilized this sample to derive phenotypes from the personality and behavioural traits assessed in a large number of individuals with eating disorders.Methods. Multivariate analytical techniques were used to characterize the relationships among personality (e.g. trait anxiety, perfectionism, harm avoidance, novelty seeking) and behavioural traits (obsessions and compulsions) in individuals with eating disorders (primarily AN; N = 348) and assess the effectiveness of these traits in classifying subjects into diagnostic subtypes.Results. Factor analysis revealed that the most influential factor was one of trait anxiety, harm avoidance, perfectionism, obsessive–compulsive behaviours, and diminished self-directedness, although the precise nature of this factor differed slightly across sites. Discriminant analysis was used to evaluate the utility of these personality/behavioural factors in predicting subdiagnosis. Overall, the misclassification rate was 34 %; however, there was an 80 % rate of accurate classification of those individuals with a diagnosis of restricting-type AN.Conclusions. Trait anxiety, harm avoidance, perfectionism, obsessive–compulsive behaviours and diminished self-directedness may best be conceptualized as parts of the same underlying construct among individuals with eating disorders, particularly AN. These personality and behavioural traits were also found to be of some utility in classifying eating disordered individuals into diagnostic subgroups, particularly those with restricting-type AN. We expect these phenotypic findings to benefit our ongoing search for genetic loci underlying the liability to eating disorders.

Background A mannosyltransferase gene (ALG9, DIBD1) at chromosome band 11q23 was previously identified to be disrupted by a balanced chromosomal translocation t(9;11)(p24;q23) co-segregating with bipolar affective disorder in a small family. Inborn ALG9 deficiency (congenital disorders of glycosylation type IL) is associated with progressive microcephaly, seizures, developmental delay, and hepatomegaly. It is unknown whether common variations of ALG9 predispose to bipolar affective disorder.

Although association analysis is a useful tool for uncovering the genetic underpinnings of complex traits, its utility is diminished by population substructure, which can produce spurious association between phenotype and genotype within population-based samples. Because family-based designs are robust against substructure, they have risen to the fore of association analysis. Yet, if population substructure could be ignored, this robustness can come at the price of power. Unfortunately it is rarely evident when population substructure can be ignored. Devlin and Roeder recently have proposed a method, termed "genomic control" (GC), which has the robustness of family-based designs even though it uses population-based data. GC uses the genome itself to determine appropriate corrections for population-based association tests. Using the GC method, we contrast the power of two study designs, family trios (i.e., father, mother, and affected progeny) versus case-control. For analysis of trios, we use the TDT test. When population substructure is absent, we find GC is always more powerful than TDT; furthermore, contrary to previous results, we show that as a disease becomes more prevalent the discrepancy in power becomes more extreme. When population substructure is present, however, the results are more complex: TDT is more powerful when population substructure is substantial, and GC is more powerful otherwise. We also explore general issues of power and implementation of GC within the case-control setting and find that, economically, GC is at least comparable to and often less expensive than family-based methods. Therefore, GC methods should prove a useful complement to family-based methods for the genetic analysis of complex traits.

OBJECTIVESTo evaluate the incidence of, and risk factors for, complications of endomyocardial biopsy in children.BACKGROUNDEndomyocardial biopsy (EMB) is a low risk procedure in adults, but there is a paucity of data with regard to performing this procedure in children.METHODSRetrospective review of the morbidity and mortality of 1,000 consecutive EMB procedures.RESULTSOne thousand EMB procedures (right ventricle 986, left ventricle 14) were performed on 194 patients from July 1987 through March 1996. Indications for EMB included heart transplant rejection surveillance (846) and the evaluation of cardiomyopathy or arrhythmia for possible myocarditis (154). Thirty-seven (4%) procedures were performed on patients receiving intravenous inotropic support. There was one biopsy related death, secondary to cardiac perforation, in a two-week-old infant with dilated cardiomyopathy. There were nine perforations of the right ventricle, eight occurring in patients with dilated cardiomyopathy and one in a transplant recipient. The transplant patient did not require immediate intervention; two patients required pericardiocentesis alone, and six underwent pericardiocentesis and surgical intervention. All nine perforations were from the femoral venous approach (p < 0.01). Multivariate analysis demonstrated that the greatest risk of perforation occurred in children being evaluated for possible myocarditis (p = 0.01) and in those requiring inotropic support (p < 0.01). Other complications included arrhythmia (5) and single cases of coronary-cardiac fistula, flail tricuspid leaflet, pneumothorax, hemothorax, endocardial stripping and seizure.CONCLUSIONSRisk of endomyocardial biopsy is highest in sick children with suspected myocarditis on inotropic support. However, EMB can be performed safely with very low morbidity in pediatric heart transplant recipients.

© 2020, The Author(s), under exclusive licence to Springer Nature Limited.Lithium is a first-line medication for bipolar disorder (BD), but only one in three patients respond optimally to the drug. Since evidence shows a strong clinical and genetic overlap between depression and bipolar disorder, we investigated whether a polygenic susceptibility to major depression is associated with response to lithium treatment in patients with BD. Weighted polygenic scores (PGSs) were computed for major depression (MD) at different GWAS p value thresholds using genetic data obtained from 2586 bipolar patients who received lithium treatment and took part in the Consortium on Lithium Genetics (ConLi+Gen) study. Summary statistics from genome-wide association studies in MD (135,458 cases and 344,901 controls) from the Psychiatric Genomics Consortium (PGC) were used for PGS weighting. Response to lithium treatment was defined by continuous scores and categorical outcome (responders versus non-responders) using measurements on the Alda scale. Associations between PGSs of MD and lithium treatment response were assessed using a linear and binary logistic regression modeling for the continuous and categorical outcomes, respectively. The analysis was performed for the entire cohort, and for European and Asian sub-samples. The PGSs for MD were significantly associated with lithium treatment response in multi-ethnic, European or Asian populations, at various p value thresholds. Bipolar patients with a low polygenic load for MD were more likely to respond well to lithium, compared to those patients with high polygenic load [lowest vs highest PGS quartiles, multi-ethnic sample: OR = 1.54 (95% CI: 1.18–2.01) and European sample: OR = 1.75 (95% CI: 1.30–2.36)]. While our analysis in the Asian sample found equivalent effect size in the same direction: OR = 1.71 (95% CI: 0.61–4.90), this was not statistically significant. Using PGS decile comparison, we found a similar trend of association between a high genetic loading for MD and lower response to lithium. Our findings underscore the genetic contribution to lithium response in BD and support the emerging concept of a lithium-responsive biotype in BD.

This study was funded by grants from the Templeton World Charity Foundation, Inc., the Medical Research Council, the Wellcome Trust, the Autism Research Trust, the Institut Pasteur, the CNRS and the University Paris Diderot. VW is funded by St. John’s College, Cambridge, and Cambridge Commonwealth Trust. The research was carried out in association with the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care East of England at Cambridgeshire and Peterborough NHS Foundation Trust. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The research was supported by the National Human Genome Research Institute of the National Institutes of Health (grant number R44HG006981). The National Science Foundation (grant numbers 0729493 and 0721707) supported the research on the Brisbane Longitudinal Twin Study. FU was supported by the British Friends of Haifa University, the Israel Science Foundation (grant no. 449/14), the British Friends of Hebrew University, and the Joseph Levy Charitable Foundation. TB was supported by the Institut Pasteur and the Bettencourt-Schueller Foundation. We thank the research participants and employees of 23andMe for making this work possible. We also thank the volunteers of the Brisbane Longitudinal Twin Study and the NIHR Cambridge BioResource.