Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders

Abstract Many neuropsychiatric disorders exhibit differences in prevalence, age of onset, symptoms or course of illness between males and females. For the most part, the origins of these differences are not well understood. In this article, we provide an overview of sex differences in psychiatric disorders including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), anxiety, depression, alcohol and substance abuse, schizophrenia, eating disorders and risk of suicide. We discuss both genetic and nongenetic mechanisms that have been hypothesized to underlie these differences, including ascertainment bias, environmental stressors, X‐ or Y‐linked risk loci, and differential liability thresholds in males and females. We then review the use of twin, family and genome‐wide association approaches to study potential genetic mechanisms of sex differences and the extent to which these designs have been employed in studies of psychiatric disorders. We describe the utility of genetic epidemiologic study designs, including classical twin and family studies, large‐scale studies of population registries, derived recurrence risks, and molecular genetic analyses of genome‐wide variation that may enhance our understanding sex differences in neuropsychiatric disorders.


| INTRODUCTION
The National Institutes of Health (NIH) mandate to consider sex differences in both human and basic research (ie, "that scientists will account for the possible role of sex as a biological variable in vertebrate animal and human studies" (notice no. NOT-OD-15-102) has led to renewed interest in studying potential hypotheses for sex differences in traits and diseases. Even though human studies of mental disorders have generally considered sex differences in etiologic and treatment studies, few basic studies of their underlying biology have investigated sex differences. The NIH mandate for inclusion of sex as a biological variable will help to align the findings from human and animal studies 1 and ultimately will assist in determining the etiology and treatment of mental disorders.
Sex differences in a disease or trait can provide insight into its causes, risk factors, and consequences. The aims of this paper are to: (a) summarize the sex-specific lifetime prevalence of the most common psychiatric disorders among adults and youth; (b) enumerate hypotheses for sex differences in mental disorders; (c) describe the use of the concepts and tools of genetic epidemiology to evaluate sex differences in psychiatric disorders and (d) examine how traditional family and twin studies, and case-control genome-wide association studies (GWAS) can help to elucidate the etiology of psychiatric disorders in the molecular era. In examining the sex-specific presentation of psychiatric disorders, we will consider sex differences in lifetime prevalence, onset, severity and/or clinical manifestations of these conditions. The hypotheses put forth to explain sex differences in mental disorders include artifactual or methodological differences in the studies or samples, differential expression or severity of disorders in males and females, sex differences in developmental trajectories, environmental factors, and different genetic architecture of the condition in males and females. As described below, the tools of genetic epidemiology, including family and twin study designs, can be used to evaluate potential explanations for sex differences, and may provide insight into the roles of both genetic and environmental factors in disease etiology.

| SEX DIFFERENCES
Sex differences in the prevalence of mental disorders have long been established. [2][3][4][5] Irrespective of the absolute rates of disorders, the sex ratio for specific classes of mental disorders is quite consistent in community surveys of both youth and adults. Table 1 presents sex differences in lifetime prevalence, onset, and severity or clinical manifestations of psychiatric disorders. As described in Table 1  are substantially greater in males than females. Rates of some of the consequences of psychiatric disorders such as completed suicide are also higher among men than women (M:F 3.9). 9 Figure 1 displays the sex ratios for all of the disorders listed in Table 1.

| Sex differences in developmental trajectories
The sex ratio for many psychiatric disorders changes across development. In childhood, males have higher rates of neurologic and neurodevelopmental disorders including ASD, ADHD and learning disabilities, with an average 3:1 sex ratio for these conditions. 10 Although males have higher rates of ASD than females, females may actually have greater remission or recovery from early childhood symptoms across development. 11 Rates of behavioral, or externalizing disorders, such as ADHD, ODD and CD, are higher in males in childhood, and the male preponderance continues into adulthood, with a steeper increase in prevalence with increasing age. 12 Similarly, during adolescence males and females initiate substance use at comparable rates, but males increase use faster than females. 13 By contrast, prospective community studies (eg, The Great Smoky Mountains Study 14 ) have shown that the prevalence of mood and anxiety disorders (ie, internalizing disorders) tends to be similar in boys and girls prior to adolescence, but the sex ratio diverges at adolescence with females having higher rates throughout adulthood. 15 Bulimic symptoms also differ between boys and girls across development. Prospective research that shows an increase in symptoms in girls between ages 14 and 16, but a decrease among boys across the same period. The severity of bulimic symptoms is greater for girls across all ages. 16 Symptoms of ADHD also change throughout development, especially for males, who tend to exhibit more hyperactivity and impulsivity in childhood. During adolescence, the level of hyperactivity-impulsivity in boys declines to the same level as girls, whereas inattentive symptoms are similar in males and females and steady across development. 17

| Artifactual or methodologic
The unequal sex ratio for several of the classes of mental disorders could be due to various methodological factors including ascertainment biases, differential reporting or recognition by males and females or factors associated with assessments that preferentially identify symptoms/disorders by sex. Ascertainment biases in clinical samples in psychiatry have been well-recognized, 25 and the large-scale community surveys of both adults and children have showed biases in severity and comorbidity of clinical samples, and under-or-overrepresentation by sex. Artifactual differences could also be due to misclassification based on symptom presentation or severity, and social or cultural differences in the recognition and interpretation of symptoms. For example, the higher rate of hyperactivity symptoms in males noted above may contribute to the higher rate of ADHD diagnoses in males. A longitudinal cohort study that tracks sex-specific incidence throughout the period of risk in a community based or highrisk sample would be one approach to test whether the deviant sex ratio for a particular disorder is a result of sampling or diagnosis. For example, depressive symptoms present equally in boys and girls in childhood, and the nearly 2-fold increase among depressive symptoms among women only appears postpubertally. 26 Therefore, sex differences in the course or trajectory of depression that have been shown in longitudinal cohort studies 27,28 may not be evident in a crosssectional examination.
In general, females are more likely to report symptoms and to utilize medical services. 24 Sex differences in the recognition or reporting of symptoms of a disorder have been widely studied for mental disorders, particularly depression. Women have been shown to be more aware of psychological symptoms, and to report those that are present. 29 Sociocultural factors may also lead to reduction of reporting of symptoms in males. For example, some depressed men may attempt to hide their emotions and appear to be angry or aggressive instead of sad, which may lead to lack of recognition of depressed mood. 30

| Environmental factors
The most obvious hypothesis for the increased risk of mood and anxi- to the timing and dose of exposure to sex steroids, and the production of testosterone in male fetuses has been shown to induce sexual differentiation in the brain. Specifically, rodent studies have showed that even though female fetuses do not produce testosterone, they do respond to exogenous testosterone in the prenatal environment (ie, from male littermates), and remain sensitive to its masculinizing effects for a longer time than males, even postnatally. 33 For twin pregnancies, sex of the co-twin has even been proposed to influence manifestations of neurodevelopmental disorders through effects on the intrauterine environment. For example, Eriksson and colleagues 34 investigated whether elevated levels of testosterone in utero increase the risk of developing ASD or ADHD traits, by assuming fetuses with a male co-twin will be exposed to higher levels of endogenous testosterone than fetuses with a female co-twin, leading to greater masculinization of the brain. Their data did not support this hypothesis, and instead they reported that presence of a female co-twin corresponded to a greater risk for ASD or ADHD traits. 34 Recent advances in neuroscience suggest that the female brain may exhibit greater plasticity in response to challenges. 35 This would be expected to lead to lower prevalence of cognitive dysfunction or other disorders, such as ASD, which may be influenced by such environmental exposures. In fact, one study demonstrated testosterone levels in boys mediated prefrontal-hippocampal covariance, but this was not shown in girls. 36 Differential exposure or reactivity to postnatal environmental factors between males and females could also contribute to sex differences in mental disorders across the lifespan. With respect to other body systems, data suggest that females may suffer from more detrimental effects of smoking (eg, developing chronic obstructive pulmonary disease, COPD), 23 and alcohol misuse 37 than do males. More recently, sex differences in the microbiome have been proposed to protect males against autoimmune disorders. 38 Differential susceptibility to environmental exposures across the lifetime should also be considered in examining causes of sex differences in psychiatric disorders. For example, women are twice as likely as men to experience posttraumatic stress disorder (PTSD), even though men and women are exposed to traumatic events at approximately equal rates. However, the type of traumatic event varies by sex; women are more likely to experience intimate partner violence, sexual assault and childhood maltreatment, while men are more likely to have experienced accidental injury, nonsexual physical assault and war-related events. 39 Differences in exposure or reactivity to environmental factors have also been widely studied as an explanation for increased rates of mood disorders among females. Women have tended to experience higher rates of sexual abuse as children and interpersonal violence as adults, as well as other interpersonal stressors, including societal gender inequality and discrimination. 40 Women may also be more predisposed to mood disorders due to increased psychological sensitivity and lower self-esteem than men. 40 In contrast, men have been shown to experience a need to conform to specific masculine gender roles that may inhibit their reporting of depressive or anxiety symptoms due to implications for perceived weakness, or strength. 41 This underreporting may also reduce treatment-seeking behavior in men. 41 There is also evidence that similar life events may have differential influences on mood disorders in males and females. Using the opposite sex twin approach (discussed below), Kendler and colleagues 42 found that whereas acute stressors and prior depression and behavioral disorders were associated with depression in males, interpersonal relationships combined with temperamental factors had greater influence in the onset of depression in females.

| Genetic factors
The role of genetic factors in sex differences in a trait or disorder will differ according to the genetic architecture of the condition. Based on our current understanding, we anticipate that most common psychiatric disorders are polygenic and reflect the combined contributions of hundreds or thousands of genes 43 with a small subset of individuals having rare variants of larger effect, such as Fragile X in ASD or chromosome 22q11 deletion in schizophrenia. Genetic factors may contribute to sex differences either through the systematic differences between males and females in sex chromosome composition or through genotype-by-sex interactions resulting in differential impact of identical autosomal genetic variants in males and females.

| Sex chromosomes
An obvious genetic hypothesis for sex differences in a heritable trait or disorder is that it is a manifestation of genes on the sex chromosomes. X-linked inheritance is one of the most important sources of sex differences in disease. In fact, early work in the familial transmission of bipolar disorder were consistent with X-linkage, 44 that is, a lack of male-to-male transmission, and an increased risk of disease in female relatives. 45 Sex chromosome aneuploidies (SCA) may provide insight into the sex-chromosome impact on sex differences in psychiatric disorders. In particular, if risk of a disorder tracks with the dosage of X or Y chromosomes, this could suggest a mechanism for observed male-female differences. As described by Green and colleagues, 46,47 sex chromosome number has been associated with a range of behavioral phenotypes, and can provide clues to sex chromosome effects on neurodevelopment. Printzlau and colleagues 48 describe the cognitive, behavioral and neural correlates of sex chromosome aneuploidies. On average, people with sex chromosome aneuploidies have greater prevalence rates of ASD and ADHD, as well as cognitive deficits as measured by full-scale, verbal and performance IQ. 48 However, brain volume differences are more variable, with some evidence that dosage of the X chromosome is related to reduced brain volume (eg, greater reduction in XXY, XXX and XXYY carriers compared with XY and XX, but no brain volume differences in XO and XYY carriers). 48 X-inactivation (lyonization), the compensatory mechanism by which balanced gene dosage is achieved between (XY) males and (XX) females is another important concept in investigating sex differences in disease. In general, there is random inactivation of one X chromosome that varies in each cell. However, one intriguing finding that is worthy of further study is the extent to which some genes escape Xinactivation. 49 Approximately 15% of genes on the X chromosome are not inactivated in females. Among males no differences in expression levels between escape genes and inactivated genes have been reported; however, the degree to which escape genes are inactivated in females varies between cells, tissues, genes and individuals. 50 Moreover, it is theorized that genes outside of the pseudo-autosomal region must be upregulated on the male X in order to maintain function. 48 Xinactivation escape genes have been associated with cognitive impairment, 51 and a recent report shows an association between genes that escape X inactivation and sex differences in the prevalence of comorbid musculoskeletal pain and posttraumatic stress symptoms after motor vehicle accidents. 52 There has been little study of the role of X inactivation in psychiatric disorders, but given the established association of inactivation with cognitive impairment and the known role of cognitive function as an endophenotype for some psychiatric disorders, this is a mechanism that deserves further consideration.
One widely studied specific sex chromosome alteration that has been associated with neuropsychiatric conditions is Fragile X syndrome (FXS), which is caused by the expansion of a trinucleotide repeat in the Fragile X Mental Retardation 1 (FMR1) gene on the X chromosome. In addition to being the most common inherited cause for ASD and intellectual disability, deletion of the FMR1 gene is also associated with a broad range of neuropsychiatric outcomes in both youth and adults ranging from anxiety disorders to substance abuse. 53 Studies of female carriers of the Fragile X mutation have also informed sex differences in the influence of these mutations. 54 Premutation carriers of the FMR1 gene have a lesser number of repeats (55-200 CGG repeats) than those who manifest FXS (>200 CGG repeats), and increased prevalence of anxiety, depression, ASD, ADHD, intellectual and learning disabilities, substance use problems, and personality disorders have been reported. 53,55 In addition, a number of X chromosome genes and copy number variants (CNV) have been associated with intellectual disability, 56 developmental delay, 57 and schizophrenia, 58 but the risk of incurring a mutation associated with intellectual disability on the X chromosome is the same for males and females.
Another severe X-linked neurodevelopmental disorder is Rett syndrome (RTT), that is caused by mutations in the transcriptional regulator MECP2, an X chromosome gene. Similar to FXS, symptoms typically include language delays, motor coordination problems and repetitive movements. 59 Originally Rett was thought to be fatal in males, and only manifested in females. However, like other X chromosome genes, MECP2 is subject to X-inactivation, and most affected individuals are female heterozygotes who display cellular mosaicism for normal and mutant MECP2. Males rarely survive, but those who do, and are hemizygous for mutant MECP2 are more severely affected than heterozygous females. 60

| Multifactorial polygenic model
With growing evidence for the polygenicity of mental disorders, 61 sex differences in the prevalence of disorders could also reflect differences in thresholds for manifestation of mental disorders based on differential accumulation of risk factors for these conditions, as proposed by the multifactorial polygenic threshold model (see Falconer, described below). 62 In summary, sex differences in the rate and presentation of psychiatric disorders reported in studies to date may be due to an artifact of reporting, sampling bias, or true male-female differences in their incidence or prevalence. Sex differences may also be the result of differential impact of pre-or post-natal environmental exposures, genetic effects arising from sex chromosome composition, or differing polygenic liability thresholds in males and females.

| APPLICATIONS OF GENETIC EPIDEMIOLOGY METHODS TO STUDY POTENTIAL EXPLANATIONS FOR SEX DIFFERENCES
The sub-discipline of genetic epidemiology focuses on identification of This model was modified to test sex differences in the liability to a condition by applying separate thresholds for males and females by Carter, 66 depicted in Figure 2 by light gray for males and dark gray for females. 66 To test whether there is a sex difference in the transmission of a disorder, it is expected that the less frequently affected sex will have a higher threshold of liability for the disorder (ie, they require a greater number of genetic and/or environmental risk factors before manifesting the disorder than the more frequently affected sex). This implies that there is greater loading of risk factors among relatives of the less commonly affected sex, so their relatives would be more likely to manifest the disorder. This expectation can be tested systematically in family and twin studies through analysis of sex of proband effects as described below. 61

BOX 1 Genetic epidemiology terminology
Heritability: The extent to which variation in a trait is due to variation in genetic factors.
Broad-sense heritability: H 2 = V G /V P , the proportion of the overall phenotypic variation (V P ) due to genetic values (V G ) that may include additive, dominance and epistasis effects.
Narrow-sense heritability, h 2 = V A /V P , the proportion of phenotypic variation that is due to additive genetic values (V A ).
Familial relative risk: Disease risk in relatives of cases vs controls.
Genetic attributable risk: The proportion of risk for a disease that would be eliminated if a particular gene or genes were not involved in the disease.
Threshold liability model: Disease model proposed by Falconer (1965) that posits a continuous underlying liability to a disease, ranging from 0 to 1, based on additive cumulation of many genetic and environmental risk factors, with a threshold that defines the point after which the disease is manifest.
Sex-dependent liability model: Disease model proposed by Carter (1969), wherein one sex requires a greater genetic liability to manifest a disease.
Genetic epidemiologic study designs can be used to examine the extent to which genetic factors may explain sex differences in a trait or disease. In light of the evidence that most psychiatric disorders are multifactorial and polygenic, investigation of sex differences in transmission can be accomplished through application of the general multifactorial model of disease transmission, shown in of ASD has been attributed to the higher tolerance for mutational burden in females that has a protective influence on the development of ASD. 82,83 Evidence for this female-protective effect in ASD has been showed in population-based, 84 family-based, [85][86][87] and cohort studies. 88 The female-protective effect has also been shown in ADHD, 89 and may also apply to schizophrenia. 90 107 These studies did not show sex differences in the heritability of ASD. Sex differences may also differ across development.
For example, because females have lower persistence rates of ASD, 11 the sex ratio may differ in cross sectional studies as compared with studies of the trajectories of ASD across the life span. This may also apply to ADHD, because twin studies of ADHD have shown that the heritability of ADHD in youth is greater than that in adults. 108 Prospective twin studies have shown that different genes may be associated with baseline symptoms compared with persistence of ADHD across development, but few of these studies have investigated interactions with sex. 109 However, in contrast to family studies, twin studies of ADHD have found equal magnitude of heritability in males and females.
In summary, studies of familial transmission and twin concordance can be used to test hypotheses regarding differential genetic liability thresholds in males and females, different genes contributing to risk in males and females and differential expression of the disorders in males and females.

| GWAS/SNPs
With advances in the identification of polymorphic markers across the human genome, the case-control study design has become increasingly popular in psychiatric genetics with sample sizes in some studies greater than 900 000 individuals. The Psychiatric Genomics Consortium (PGC, https://www.med.unc.edu/pgc/) has conducted genomewide meta-and mega-analyses for multiple psychiatric disorders including ADHD, ASD, bipolar disorder, major depression and schizophrenia. Yet, sex differences in genetic architecture of these conditions has received relatively little attention. For example, the most recent GWAS that identified 102 variants associated with depression, controlled for sex as a potential confounding variable rather than examining its effect directly. 110 The CONVERGE Consortium study of recurrent depression was restricted to female participants; however, the replication had participants of both sexes. 111 Controlling for sex by including it as a covariate in GWAS is far more common than explicitly examining the effect of sex. In 2017, Powers and colleagues 112 reported that only 1% of genetic association studies of any disease had reported sex differences, and an even smaller proportion considered sex chromosomes. There is an emerging number of studies that have reported sex differences in the findings from GWAS of psychiatric disorders. Table 2 presents a summary of findings of recent GWAS that have presented sex stratified analyses, the number of genome-wide sexspecific significant SNP associations, and sex-specific SNP based heritability (h 2 SNP ). There are significant sex differences for ADHD, 95 alcohol dependence, 113 ASD, 114 anorexia, 115 Major Depressive Disorder (MDD), 116 Obsessive-Compulsive Disorder (OCD), 117 PTSD, 118 and substance use disorder. 119 Sex stratified GWAS have not been published for anxiety disorders, bipolar disorder or schizophrenia. However, there may be studies that have completed sex-stratified analyses but did not report the findings if they were negative. 120 Two approaches have been used to investigate sex differences in GWAS: (a) estimation of heritability using either genomic relatedness matrix restricted maximum likelihood (GREML), or linkage disequilibrium score regression, (LDSC) and (b) calculation of sex-specific PRS, an average of risk alleles across the genome weighted by effect size and statistical significance. 121 Hall and colleagues 116

| Rare variants and CNVs
In recent years, more work has been completed to establish the role of rare genetic variants in neuropsychiatric disorders, 87,125,126 including single nucleotide variants (SNVs) from whole genome or whole exome sequencing and CNVs, which can be either de novo or inherited mutations. Although these variants occur at low frequency, it is assumed that they would have a large effect. 127 As described previously, there has been shown to be a "female-protective effect" in ASD, which is supported by the higher incidence of these high impact rare variants among affected females than affected males. 128 While we have concentrated on genotype variation in our discussion of molecular genetic studies of sex differences in psychiatric phenotypes, other "omics" domains may also play a role. Modifications, such as DNA methylation may have an impact on sex differences. In fact, Maschietto and colleagues 129 postulated that a primary driver of sex differences in neuropsychiatric disorders is differential DNA methylation of autosomes by sex. The majority of the work in this area has been conducted in rodents, where it has been showed that DNA methylation plays a role in establishing sex differences in the brain during development, while profiles of epigenetic changes by sex during brain development in humans are not yet readily available. 130 Differential gene expression patterns have been reported in male and female postmortem brain tissue, although it is unclear whether the expression and methylation differences result from, or are in the etiologic pathway of neuropsychiatric disorders. 131  in the establishment of brain differences across development, and sex differences in regional brain volumes due to differential cell death, neuronal and glial genesis, dendritic branching and synaptic patterning between males and females. There are several strategies that may be employed to identify the role of genetic and environmental factors in the core domains underlying mental disorders. By integrating advances in neuroscience to study hypotheses for sex differences we can glean more information about how the sex differences in the brain lead to different sex ratios in complex disorders. Moreover, these studies may aid in identifying critical periods of risk, when exposure to environmental factors may influence genetic susceptibility factors, such as the prenatal period for neurodevelopmental disorders, middle childhood for ADHD, and adolescence and early adulthood for mood disorders. Studies of sex differences could also be more informative if they also considered sex differences in disease subtypes, age at onset, treatment response and other potential sources of heterogeneity.
Sex differences are also clearly important in pharmacologic treatment, yet females are not well represented in clinical trials. In fact, between 1997 and 2001, the majority of prescription drugs removed from the market (8/10) showed greater adverse effects in females. 133 A salient example of this is a recommendation from the Food and Drug Administration (FDA) that the dosage of the sedative zolpidem be halved in women. 134 This recommendation followed anecdotal evidence of impaired driving the morning after taking zolpidem among women. 135 The ultimate decision was based on clinical trial data, as well as driving simulation studies. 136 In this instance, it is assumed that women and men metabolize this compound differently, and this should have been established in earlier work.
To date, it is difficult to interpret the data regarding sex differences in the genetic architecture of psychiatric disorders, due to differences across studies in ascertainment and methods, which have Family study data are central to establishment of the origin of mutations, that is, inherited or de novo, from both sequencing and structural variation data, and play a vital role in establishing the inheritance of both phenotypes and genotypes across generations. 137 Evaluation of families will allow for the evaluation of both common and rare variants, as well allowing researchers to evaluate environmental risk factors in a way that is not possible in case-control studies. Specifically including sex differences in the study design and prospectively studying sex differences across development in families will be vitally important to examining potential genetic and environmental mechanisms for sex differences. Systematic recruitment by sex of the proband and prospective designs that examine the sex-ratio and potential influences across development may provide insight not only on the emergence of sex differences but also their underlying causes. Prospective studies that systematically build sex into the design to study the longitudinal evolution of sex differences in males and females are needed. For example, in a prospective study of the course of young children at the initial diagnosis of ASD, Szatmari and colleagues 11 showed that the sex of the affected child with ASD was the only significant predictor of differential trajectories of symptoms of ASD over time.
They found that boys had more stable, severe symptoms over time, whereas girls exhibited less severe symptoms and improvement over time. In fact, some girls no longer manifest the cognitive and language problems at follow up. This illustrates that the age or developmental stage at ascertainment of a condition may influence the sex ratio. Developmental studies of sex differences across the life course will also aid in our understanding of the factors underlying these differences. Biologic and social factors in early life development, such as parenting style or social environment, have long been seen as clinically relevant to later adult psychopathology, 133 but there remains a dearth of information on how these early factors may differentially impact the sexes.
Family history information is not typically collected in casecontrol GWAS, because detailed family interviews of psychiatric disorders is generally beyond the scope of large sample size case-control GWAS and health registry studies. However, enrichment of these large-scale studies through systematic collection of family history information could inform our understanding of sex differences in the genetics of neuropsychiatric disorders, by enabling the examination of sex-based rates and transmission in the family. Collection of family history in electronic health records (EHR) is typically limited to identification of affected cases from the clinical notes without denominators (ie, "Does anyone in your family have depression/alcohol abuse/etc.?" without enumerating family members) precluding estimation of recurrence risks. 144 However, an exemplary study that mined emergency contact data from the next-of-kin contact information in the EHR to identify familial relationships with validation of the EHR next-of-kin relationships through genetically calculated kinships computed heritability estimates for a range of clinical conditions. They reported a median heritability of 0.41 (ICD-9) and 0.31 (ICD-10) for mental health disorders, but note in their discussion that mental health conditions are generally not well documented in EHRs. 145 In fact, only moderate agreement has been reported for mental health diagnoses from administrative data, that is where an ICD, DSM or other similar reference standard diagnosis is compared with psychiatric diagnoses in routinely recorded data (median kappa = 0.45-0.55). 146 Large-scale population registries will provide a valuable resource for identifying the role of sex differences in the prevalence, course and role of genetic and environmental risk factors for mental disorders.
Moreover, systematic collection of additional family history information, including enumeration of family members, in large scale casecontrol studies could inform our understanding of sex differences in the genetic architecture of neuropsychiatric disorders.

| CONCLUSION
Sex differences of some kind-in prevalence, age at onset or presentation-have been demonstrated for a large portion of major psychiatric disorders. These may be due to some combination of artifact, differential susceptibility to environmental insults in males and females, effects of sex chromosome composition or differential nature and impact of genetic effects in males and females. Genetic epidemiologic studies have identified differences in heritabilities of several disorders between males and females and have provided support for a higher burden of genetic risk in the less affected sex in some cases. Molecular genetic studies have showed different SNPs associated with a disorder in males and females or differing strengths of SNP effects in males and females, and have also provided support for differing heritabilities or burden of risk alleles by sex. However, no consistent patterns have emerged across disorders and for the most part the mechanisms underlying sex differences in psychiatric disorders remain unexplained.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.