Family Linkage Research Articles

Novel mutations in the genes TGM1 and ALOXE3 underlying autosomal recessive congenital ichthyosis

Ichthyoses are clinically characterized by scaling or hyperkeratosis of the skin or both. It can be an isolated condition limited to the skin or appear secondarily with involvement of other cutaneous or systemic abnormalities. The present study investigated clinical and molecular characterization of three consanguineous families (A, B, C) segregating two different forms of autosomal recessive congenital ichthyosis (ARCI). Linkage in three consanguineous families (A, B, C) segregating two different forms of ARCI was searched by typing microsatellite and single nucleotide polymorphism marker analysis. Sequencing of the two genes TGM1 and ALOXE3 was performed by the dideoxy chain termination method. Genome-wide linkage analysis established linkage in family A to TGM1 gene on chromosome 14q11 and in families B and C to ALOXE3 gene on chromosome 17p13. Subsequently, sequencing of these genes using samples from affected family members led to the identification of three novel mutations: a missense variant p.Trp455Arg in TGM1 (family A); a nonsense variant p.Arg140* in ALOXE3 (family B); and a complex rearrangement in ALOXE3 (family C). The present study further extends the spectrum of mutations in the two genes involved in causing ARCI. Characterizing the clinical spectrum resulting from mutations in the TGM1 and ALOXE3 genes will improve diagnosis and may direct clinical care of the family members.

Influence of technology in genetic epidemiology

AbstractGenetic epidemiology is the study of genetic factors and their influence on health and disease. Traditionally, these studies have been based on familial aggregation, segregation, or linkage analysis, mainly allowing the study of monogenic disorders. Advances in biotechnology have made techniques such as genome-wide association studies and next-generation sequencing possible, allowing more complex studies. In addition to the completion of large consortia projects, such as the Human Genome Project, ENCODE, and the 1000 Genome Project, these techniques make it possible to explain a higher proportion of the heritability in polygenic disorders compared to previous techniques. Here, we provide an overview of approaches to genetic epidemiology and how technological improvements have influenced experimentation in this area. These improvements have led genetic epidemiology to unprecedented advances, being excellent tools for understanding the genetic variability underlying complex phenotypes.

Genetics of Graves' Disease: Special Focus on the Role of TSHR Gene.

As most autoimmune diseases, inherited predisposition to Graves' disease (GD) is polygenic with the main contributory genes being located in the HLA region. Also, as in other autoimmune diseases, family linkage, candidate gene association, and GWAS studies have identified an expanding number of predisposing genes (CTLA4, CD40, PTPN22...) and 2 of them, TG and TSHR, are thyroid specific. In spite of this expanding number of associated genes, it has been estimated that all together they account for only a 20% of the heritability of GD. TSHR is of special interest as it codes for the target of TSHR stimulating antibodies (TSAbs), which are unequivocally pathogenic and an exception in autoimmunity by being stimulating rather than neutral, blocking, or cytotoxic. This is surprising because the generation of stimulating TSHR antibodies by immunisation of laboratory animals has been remarkably difficult, suggesting an underlying mechanism that favours stimulating over neutral or blocking anti-TSHR antibodies must be operating in GD patients. Besides, after HLA, TSHR is the gene most tightly associated to GD. The TSHR polymorphisms conferring susceptibility are located in the unusually large intron 1. Two mechanisms have been already put forward to explain its association with GD. According to one, the risk alleles determine an increase in the expression of TSHR mRNA splice variants that code for a soluble form of the receptor. The wider distribution of soluble TSHR would favour its immunogenicity and the development of an autoimmune response to it. It does not explain why it becomes immunogenic, as immunogenicity and distribution are not necessarily connected, nor why the immune response focus to the production of stimulating antibodies. According to the second mechanism proposed, the risk alleles determine a lower TSHR expression in the thymus and this would favour the escape of more TSHR reactive T cells, that is, central tolerance failure. The unexpected finding that thymocytes express TSHR and that TSAbs stimulate them lead to postulate that this would accelerate their egress from the thymus and a less efficient deletion of the TSHR self-reactive T cells. It can be envisaged that these autoreactive T cells may enhance the production of TSHR-Abs in the germinal centres of the thyroid draining lymph nodes, especially of those capable of further stimulating the egress of autoreactive T cells from the thymus. This mechanism, which does not exclude the former, provides and insight of the way in which TSAbs are favoured over neutral or blocking antibodies. Finally this would explain the frequent finding of thymic hyperplasia in GD patients.

Associations between parental chronic pain and self-esteem, social competence, and family cohesion in adolescent girls and boys--family linkage data from the HUNT study.

BackgroundParental chronic pain has been associated with adverse outcomes in offspring. However, knowledge on individual and family resilience factors in adolescent offspring of chronic pain sufferers is scarce. This study thus aimed to investigate the associations between parental chronic pain and self-esteem, social competence, and family cohesion levels reported by adolescent girls and boys.MethodsBased on cross-sectional surveys from the Nord Trøndelag Health Study (the HUNT 3 study), the study used independent self-reports from adolescents aged 13 to 18 years (n = 3227) and their parents and conducted separate linear regression analyses for girls and boys.ResultsConcurrent maternal and paternal chronic pain was associated with reduced self-esteem, social competence, and family cohesion in girls. Moreover, maternal chronic pain was associated with higher social competence in boys and reduced self-esteem in girls. The majority of the observed associations were significantly different between girls and boys. Paternal chronic pain was not found to be associated with child outcomes.ConclusionsThe findings indicate that the presence of both maternal and paternal chronic pain could be a potential risk factor for lower levels of individual and family resilience factors reported by girls. Further research on the relationship between parental pain and sex-specific offspring characteristics, including positive resilience factors, is warranted. The study demonstrates the importance of targeting the entire family in chronic pain care.

New insights from monogenic diabetes for "common" type 2 diabetes.

Boundaries between monogenic and complex genetic diseases are becoming increasingly blurred, as a result of better understanding of phenotypes and their genetic determinants. This had a large impact on the way complex disease genetics is now being investigated. Starting with conventional approaches like familial linkage, positional cloning and candidate genes strategies, the scope of complex disease genetics has grown exponentially with scientific and technological advances in recent times. Despite identification of multiple loci harboring common and rare variants associated with complex diseases, interpreting and evaluating their functional role has proven to be difficult. Information from monogenic diseases, especially related to the intermediate traits associated with complex diseases comes handy. The significant overlap between traits and phenotypes of monogenic diseases with related complex diseases provides a platform to understand the disease biology better. In this review, we would discuss about one such complex disease, type 2 diabetes, which shares marked similarity of intermediate traits with different forms of monogenic diabetes.

175 Aortopathy-causing mutations increase aortic stiffness in healthy individuals

Introduction As gene sequencing becomes more widespread, the clinical implications of incidental findings in patients’ genomes are becoming more complex. We identified healthy volunteers with mutations known to cause penetrant, Mendelian aortic disease, and examined the association of these mutations with aortic pulse wave velocity (PWV); a key marker of cardiovascular risk and aortic elastic function. Methods We recruited 476 healthy volunteers with no known history of cardiovascular risk factors or disease for aortic phenotyping and gene sequencing. We measured aortic arch pulse wave velocity derived from Cardiovascular MRI (CMR) using ArtFun software and performed whole exome sequencing (Illumina HiSeq 2000). Sequence was alignedto hg19 reference using BWA v0.7.10 and variants were called using GATK and validated using IGV. Variants that are presumed causative for aortic disease were prioritised using HGMD and were further annotated by literature review. A binary variable, reflected the presence or absence of a variant linked with aortopathy by this approach. Statistical analysis was performed using linear regression modelling, Mann-Whitney U tests and bootstrapping in R. For Mann-Whitney U tests, we used age-corrected PWV [=PWV/log (Age)]. Results 17 of our healthy volunteers (3%) had previously reported pathogenic mutations in seven aortopathy genes ( COL1A2 , COL3A1 , FBN1 , MYH11 , MYLK , TGFBR1 and TGFBR2 ; see Table 1). Three mutations (in 4 individuals; 0.8% of our cohort) had evidence for pathogenicity (eg family linkage analysis) beyond just a single case report; two in TGFBR2 (3 individuals) and one in COL1A2 . These four subjects had significantly higher aPWVs than control cases (Mann-Whitney U test; U=235, p = 0.01; see Figure 1), and than those cases where the evidence for variant pathogenicity was limited (p = 0.02). Linear regression modelling of PWV was significantly improved by the addition of AOV status (ANOVA of nested linear models; p = 0.03; F=5.56(1), R 2 =0.07; multiple R 2 =0.57; p Discussion It is not unusual to find “disease-causing” variants in an apparently healthy population. Sometimes this is used to argue against the pathogenicity of a particular variant. However, our results imply that some of these “healthy” individuals may have penetrant aortic disease but of limited expressivity. These individuals may have increased risk of cardiovascular events, and so-called “spontaneous” aortic aneurysm and dissection. This finding therefore has implications for genetic counselling, as well as for the conduct of gene sequencing studies.

Joint-multiple family linkage analysis predicts within-family variation better than single-family analysis of the maize nested association mapping population

Quantitative trait locus (QTL) mapping has been used to dissect the genetic architecture of complex traits and predict phenotypes for marker-assisted selection. Many QTL mapping studies in plants have been limited to one biparental family population. Joint analysis of multiple biparental families offers an alternative approach to QTL mapping with a wider scope of inference. Joint-multiple population analysis should have higher power to detect QTL shared among multiple families, but may have lower power to detect rare QTL. We compared prediction ability of single-family and joint-family QTL analysis methods with fivefold cross-validation for 6 diverse traits using the maize nested association mapping population, which comprises 25 biparental recombinant inbred families. Joint-family QTL analysis had higher mean prediction abilities than single-family QTL analysis for all traits at most significance thresholds, and was always better at more stringent significance thresholds. Most robust QTL (detected in >50% of data samples) were restricted to one family and were often not detected at high frequency by joint-family analysis, implying substantial genetic heterogeneity among families for complex traits in maize. The superior predictive ability of joint-family QTL models despite important genetic differences among families suggests that joint-family models capture sufficient smaller effect QTL that are shared across families to compensate for missing some rare large-effect QTL.

Advances in glaucoma genetics.

Glaucoma is presumed to be a complex progressive neurodegenerative disorder caused by genetic and environmental factors, and it is also one of the leading causes of irreversible blindness worldwide. Glaucoma is divided into two major forms: primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). Familial linkage studies for POAG have been performed and identified causative POAG disease genes (e.g., MYOC, OPTN, and WDR36). Recent genome-wide association studies revealed a large number of susceptibility gene variants associated with both POAG (e.g., CDKN2BAS, CAV1/CAV2, and ATOH7) and PACG (e.g., PLEKHA7 and COL11A1 PCMTD1-ST18). In POAG, these genes were expressed in ocular tissues including retinal ganglion cells, ciliary body, trabecular meshwork, and the optic nerve head. A further functional analysis of these genes would provide the precise mechanism underlying glaucoma, including POAG and PACG. It might be possible to assess the personal future risk for glaucoma and facilitate therapeutic strategies through genetic studies.

β-Globin gene cluster haplotypes of Hb D-Los Angeles in Mazandaran Province, Iran.

Several types of hemoglobin D (Hb D) are distinguishable by DNA analysis, and the aim of this study was to identify the types of Hb D variant and β-globin gene haplotypes linked to Hb D in Mazandaran Province, northern Iran. Fifty five individuals were identified as Hb D carriers, and PCR-RFLP analysis revealed that all 55 had the Hb D-Los Angeles type. To identify haplotypes associated with the β(D) allele, family linkage analysis, using the PCR-RFLP method for seven polymorphisms in the β-globin gene cluster, was carried out on families of 23 of these 55 individuals. We observed three different haplotypes in association with Hb D-Los Angeles. In most cases (91.4%) β(D) alleles were linked to haplotype I [+ - - - - + +]. Haplotype II [- + + - + + +] and an atypical haplotype [- + + - - + -] were each in association with the β(D) allele in only one case (4.3%). This is the first report worldwide of the [- + + - - + -] haplotype in association with Hb D-Los Angeles. We conclude that more than 90% of the evaluated Hb D-Los Angeles alleles in Mazandaran have the same origin, and the two rare haplotypes may represent different genetic origins and/or other molecular events, such as gene conversion or recombination, in the region.

Neck/upper back and low back pain in parents and their adult offspring: Family linkage data from the Norwegian HUNT Study.

Chronic pain in the neck and low back is highly prevalent. Although heritable components have been identified, knowledge about generational transmission of spinal pain between parents and their adult offspring is sparse. This study examined the intergenerational association of spinal pain using data from 11,081 parent-offspring trios participating in the population-based HUNT Study in Norway. Logistic regression was used to calculate adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for offspring spinal pain associated with parental spinal pain. In total, 3654 (33%) offspring reported spinal pain at participation. Maternal and paternal spinal pain was consistently associated with higher ORs for offspring spinal pain. The results suggest a slightly stronger association for parental multilevel spinal pain (i.e., both neck/upper back pain and low back pain) than for pain localized to the neck/upper back or low back. Multilevel spinal pain in both parents was associated with ORs of 2.6 (95% CI, 2.1-3.3), 2.4 (95% CI, 1.9-3.1) and 3.1 (95% CI, 2.2-4.4) for offspring neck/upper back, low back and multilevel spinal pain, respectively. Parental chronic spinal pain was consistently associated with increased occurrence of chronic spinal pain in their adult offspring, and this association was particularly strong for multilevel spinal pain.

A novel deletion mutation in theDSG4gene underlies autosomal recessive hypotrichosis with variable phenotype in two unrelated consanguineous families

Autosomal recessive hypotrichosis is a rare human hereditary disorder presenting as sparse scalp hair or as woolly hair occurring on various parts of the body. Various forms of isolated hypotrichosis have been reported to date. Mutations in at least 11 genes have been reported to cause hypotrichosis. To investigate the clinical and genetic basis of autosomal recessive hypotrichosis in two unrelated consanguineous families. Genotyping by highly polymorphic microsatellite markers established linkage in both families to the DSG4 gene on chromosome 18q21. PCR amplification of exons and intron-exon borders of the DSG4 gene was performed, and the products sequenced to search for disease-causing sequence variants. Clinical investigation revealed typical hypotrichosis in the affected members of one family, while other affected members showed presence of monilethrix-like scalp hair. Sequence analysis of DSG4 revealed a novel deletion mutation (c.85-1_191del) in the affected subjects of both families. This study further extends the body of evidence that mutations in the DSG4 gene result in both hypotrichosis and monilethrix-like scalp hair.

Analysis of POFUT1 gene mutation in a Chinese family with Dowling-Degos disease.

Dowling-Degos disease (DDD) is an autosomal dominant genodermatosis characterized by reticular pigmented anomaly mainly affecting flexures. Though KRT5 has been identified to be the causal gene of DDD, the heterogeneity of this disease was displayed: for example, POFUT1 and POGLUT1 were recently identified and confirmed to be additional pathogenic genes of DDD. To identify other DDD causative genes, we performed genome-wide linkage and exome sequencing analyses in a multiplex Chinese DDD family, in which the KRT5 mutation was absent. Only a novel 1-bp deletion (c.246+5delG) in POFUT1 was found. No other novel mutation or this deletion was detected in POFUT1 in a second DDD family and a sporadic DDD case by Sanger Sequencing. The result shows the genetic-heterogeneity and complexity of DDD and will contribute to the further understanding of DDD genotype/phenotype correlations and to the pathogenesis of this disease.

Whole exome sequencing for familial bicuspid aortic valve identifies putative variants.

Bicuspid aortic valve (BAV) is the most common congenital cardiovascular malformation. Although highly heritable, few causal variants have been identified. The purpose of this study was to identify genetic variants underlying BAV by whole exome sequencing a multiplex BAV kindred. Whole exome sequencing was performed on 17 individuals from a single family (BAV=3; other cardiovascular malformation, 3). Postvariant calling error control metrics were established after examining the relationship between Mendelian inheritance error rate and coverage, quality score, and call rate. To determine the most effective approach to identifying susceptibility variants from among 54 674 variants passing error control metrics, we evaluated 3 variant selection strategies frequently used in whole exome sequencing studies plus extended family linkage. No putative rare, high-effect variants were identified in all affected but no unaffected individuals. Eight high-effect variants were identified by ≥2 of the commonly used selection strategies; however, these were either common in the general population (>10%) or present in the majority of the unaffected family members. However, using extended family linkage, 3 synonymous variants were identified; all 3 variants were identified by at least one other strategy. These results suggest that traditional whole exome sequencing approaches, which assume causal variants alter coding sense, may be insufficient for BAV and other complex traits. Identification of disease-associated variants is facilitated by the use of segregation within families.

Disease-related mutations among Caribbean Hispanics with familial dementia.

Pathogenic mutations in the three known genes – the amyloid precursor protein (APP), presenilin 1 (PSEN1), presenilin 2 (PSEN2) – are known to cause familial Alzheimer's disease (AD) and tend to be associated with early-onset AD. However, the frequency and risk associated with these mutations vary widely. In addition, mutations in the frontotemporal lobar degeneration (FTLD) genes – the microtubule-associated protein tau (MAPT), granulin (GRN) – have also been found to be associated with clinical AD. Here, we conducted targeted resequencing of the exons in genes encoding APP, PSEN1, PSEN2, GRN, and MAPT in 183 individuals from families with four or more affected relatives, presumed to be AD, and living in the Dominican Republic and Puerto Rico. We then performed linkage and family-based association analyses in carrier families, and genotyped 498 similarly aged unrelated controls from the same ethnic background. Twelve potentially pathogenic mutations were found to be associated with disease in 53 individuals in the five genes. The most frequently observed mutation was the p.Gly206Ala variant in PSEN1 present in 30 (57%) of those sequenced. In the combined linkage and association analyses several rare variants were associated with dementia. In Caribbean Hispanics with familial AD, potentially pathogenic variants were present in 29.2%, four were novel mutations, while eight had been previously observed. In addition, some family members carried variants in the GRN and MAPT genes which are associated with FTLD.

Chronic Obstructive Pulmonary Disease Genetics: A Review of the Past and a Look Into the Future.

Chronic obstructive pulmonary disease (COPD) affects over 10 million Americans.1 This complex disorder demonstrates many different presentations in a wide variety of patients, and results from a combination of environmental exposures and genetic risk factors. Smoking alone does not result in COPD: not all smokers develop COPD and lung function decline among smokers is highly variable. There is growing evidence for genetic risk factors for COPD: early familial aggregation and linkage analysis studies strongly suggested genetic contributions to COPD, and recent genome-wide association studies have identified several genomic regions that are clearly related to COPD susceptibility. However, despite recent advances in COPD genetics, much of the heritability of COPD remains unexplained, and functional studies are only beginning to elucidate a role for the genetic associations that have been identified. Despite this, the future is bright for understanding the genetics of COPD. Improvements in COPD phenotyping, collaborations among COPD study cohorts, and novel integrative approaches to identifying genetic markers all promise to unravel much of this missing heritability and ultimately lead to improvements in our understanding of COPD susceptibility and treatment.

Comparison of father-offspring and mother-offspring associations of cardiovascular risk factors: family linkage within the population-based HUNT Study, Norway

Cardiovascular risk factors are transmitted from parents to offspring; however, the relative contributions of fathers and mothers remain unclear. If maternal exposures during pregnancy influence offspring through the intrauterine environment, associations between mothers and offspring are expected to be stronger than between fathers and offspring. In this family linkage study we compared father-offspring and mother-offspring associations of several cardiovascular risk factors. The study population consisted of 36,528 father-mother-offspring trios who participated at one or more surveys of the HUNT Study, Norway in 1984-86, 1995-97 and 2006-08. Parent-offspring associations were assessed using unstandardized and standardized residuals from linear regression analysis, and possible non-paternity was accounted for in sensitivity analyses. Age- and sex-adjusted parent-offspring associations for anthropometric factors, blood pressure, blood lipids, blood glucose and resting heart rate were largely similar between fathers and mothers. Use of standardized values and analyses adjusted for non-paternity further emphasized this similarity. This study found largely similar father-offspring and mother-offspring associations across all cardiovascular risk factors under study, arguing against strong maternal effects transmitted through intrauterine mechanisms.

Symptoms of insomnia among OSA patients before and after 2years of PAP treatment

To assess the changes of insomnia symptoms among patients with obstructive sleep apnea (OSA) from starting treatment with positive airway pressure (PAP) to a two-year follow-up. All subjects underwent a medical examination, type 3 sleep study and answered questionnaires on health and sleep before and 2 years after starting PAP treatment. The change in prevalence of insomnia symptoms by subtype were assessed by questionnaire and compared between individuals who were using or not using PAP at follow-up. Symptoms of middle insomnia were most common at baseline and improved significantly among subjects using PAP (from 59.4% to 30.7%, p < 0.001). Symptoms of initial insomnia tended to persist, regardless of PAP treatment and symptoms of late insomnia were more likely to improve among subjects not using PAP. Subjects with symptoms of initial and late insomnia at baseline were less likely to adhere with PAP (odds ratio (OR) 0.56, p = 0.007, and OR 0.53, p < 0.001, respectively). PAP treatment significantly reduced symptoms of middle insomnia. Symptoms of initial and late insomnia, however, tended to persist regardless of PAP treatment and had a negative effect on treatment adherence. Targeted treatment for insomnia may be beneficial for patients with OSA comorbid with insomnia and has the potential to positively affect adherence to PAP. Support: NIH grant HL72067 for “A Family Linkage Study of Obstructive Sleep Apnoea” and HL94307 for “Endophenotypes of Sleep Apnea and Role of Obesity”, the Eimskip Fund of the University of Iceland and the Landspitali University Hospital Research Fund.

Increased decidual mRNA expression levels of candidate maternal pre-eclampsia susceptibility genes are associated with clinical severity

IntroductionPre-eclampsia (PE) has a familial association, with daughters of women who had PE during pregnancy having more than twice the risk of developing PE themselves. Through genome-wide linkage and genetic association studies in PE-affected families and large population samples, we previously identified the following as positional candidate maternal susceptibility genes for PE; ACVR1, INHA, INHBB, ERAP1, ERAP2, LNPEP, COL4A1 and COL4A2. The aims of this study were to determine mRNA expression levels of previously identified candidate maternal pre-eclampsia susceptibility genes from normotensive and severe PE (SPE) pregnancies and correlate mRNA expression levels with the clinical severity of SPE. MethodsThird trimester decidual tissues were collected from both normotensive (n = 21) and SPE pregnancies (n = 24) and mRNA expression levels were determined by real-time PCR. Gene expression was then correlated with several parameters of clinical severity in SPE. Statistical significance was determined by Mann–Whitney U test and Spearman's Correlation. ResultsThe data demonstrate significantly increased decidual mRNA expression levels of ACVR1, INHBB, ERAP1, ERAP2, LNPEP, COL4A1 and COL4A2 in SPE (p < 0.05). Increased mRNA expression levels of several genes – INHA, INHBB, COL4A1 and COL4A2 were correlated with earlier onset of PE and earlier delivery of the fetus (p < 0.05). ConclusionThese results suggest altered expression of maternal susceptibility genes may play roles in PE development and the course of disease severity.

Linkage, Mobility, and Selfishness in the MazF Family of Bacterial Toxins: A Snapshot of Bacterial Evolution

Prokaryotic MazF family toxins cooccur with cognate antitoxins having divergent DNA-binding folds and can be of chromosomal or plasmid origin. Sequence similarity search was carried out to identify the Toxin–Antitoxin (TA) operons of MazF family followed by sequence analysis and phylogenetic studies. The genomic DNA upstream of the TA operons was searched for the presence of regulatory motifs. The MazF family toxins showed a conserved hydrophobic pocket in a multibinding site and are present in pathogenic bacteria. The toxins of the MazF family are associated with four main types of cognate antitoxin partners and cluster as a subfamily on the branches of the phylogenetic tree. This indicates that transmission of the entire operon is the dominant mode of inheritance. The plasmid borne TA modules were interspersed between the chromosomal TA modules of the same subfamily, compatible with a frequent interchange of TA genes between the chromosome and the plasmid akin to that observed for antibiotic resistance gens. The split network of the MazF family toxins showed the AbrB-linked toxins as a hub of horizontal gene transfer. Distinct motifs are present in the upstream region of each subfamily. The presence of MazF family TA modules in pathogenic bacteria and identification of a conserved binding pocket are significant for the development of novel antibacterials to disrupt the TA interaction. However, the role of TAs in stress resistance needs to be established. Phylogenetic studies provide insight into the evolution of MazF family TAs and effect on the bacterial genome.

Sex differences in the genetic risk for schizophrenia: History of the evidence for sex‐specific and sex‐dependent effects

Although there is a long history to examinations of sex differences in the familial (and specifically, genetic) transmission of schizophrenia, there have been few investigators who have systematically and rigorously studied this issue. This is true even in light of population and clinical studies identifying significant sex differences in incidence, expression, neuroanatomic and functional brain abnormalities, and course of schizophrenia. This review highlights the history of work in this arena from studies of family transmission patterns, linkage and twin studies to the current molecular genetic strategies of large genome-wide association studies. Taken as a whole, the evidence supports the presence of genetic risks of which some are sex-specific (i.e., presence in one sex and not the other) or sex-dependent (i.e., quantitative differences in risk between the sexes). Thus, a concerted effort to systematically investigate these questions is warranted and, as we argue here, necessary in order to fully understand the etiology of schizophrenia.