There is a large twin literature for insomnia and other sleep phenotypes, with studies ranging across the lifespan from young child to adult samples (see [21, 77] for review). The estimated heritability of sleep phenotypes varies widely, with estimates of insomnia in adults ranging from 0.20 (overall insomnia factor; [80]) to 0.64 (insomnia; [81]). More recently, the longitudinal stability of insomnia heritability in adults has been demonstrated, with findings suggesting that the majority of the genetic influence on insomnia symptoms comes from latent genetic effects as opposed to time-specific sources [82]. There are several twin studies of high relevance to this chapter. First, McCarren and colleagues [83] conducted the only twin study of sleep in veterans, utilizing data on four sleep-related phenotypes and a composite score from 2825 male twin pairs in the VET Registry. Heritability estimates were 0.28 (trouble falling asleep a ² = 0.28), 0.26 (waking up several times per night a ² = 0.26), 0.42 (trouble staying asleep), 0.21 (feeling tired after usual amount of sleep a ² = 0.21), and 0.28 (composite ordinal score). Combined analyses also incorporated combat exposure severity, in addition to additive genetic effects, but this did not alter the genetic contributions to sleep variables. Combat exposure was weakly related to all sleep variables; however, PTSD was not examined in this study and requires future investigation.

Second, there is a subset of the literature that explores genetic overlap between sleep and common psychopathology. There is some evidence for overlap between sleep and internalizing disorders (depression, anxiety), with many studies using child and adolescent samples [84–87]. Estimates of genetic overlap with internalizing psychopathology range from partial (genetic correlations less than 1; [86]) to complete (i.e., the genetic contribution overlapped completely; [87]). None of these studies included externalizing disorders, and the literature on this overlap is limited. However, results from our group, in the first study to examine overlap between sleep and diagnoses of both types of psychopathology in an adult sample, show substantial (greater than 50%) genetic overlap between insomnia and depression, complete genetic overlap between insomnia and anxiety, and partial genetic overlap between insomnia and externalizing disorders (alcohol abuse and dependence, antisocial personality disorder) [88]. Twin studies show that the genetic influences on PTSD, like those on insomnia, overlap significantly with internalizing disorders, with some research showing complete genetic overlap between MDD and PTSD [89–92]. Additionally, PTSD shows modest genetic overlap with externalizing psychopathology [92]. Given this, it is reasonable to expect that there is significant genetic overlap between sleep and PTSD, although no studies to date have specifically examined this relationship.

Finally, as nightmares are a common symptom of PTSD, it is important to discuss their heritability. However, note that twin studies of nightmares do not examine them in the context of PTSD or in trauma-exposed samples. In a sample of Finnish twins, Hublin and colleagues [93] examined the heritability of childhood and adult nightmares (retrospectively reported). Results suggested a moderate heritable component for childhood nightmares (a ² ~ 0.35–0.52) in both sexes, and in adulthood a sex difference was found in that the heritability estimate was higher in women than men (combined sexes: a ² ~ 0.27–45). Another study of children and adolescents estimates nightmare heritability around 50% and shows that it does not overlap with anxiety symptoms [94].

Numerous thorough reviews have been dedicated to the molecular genetics of sleep and circadian rhythms [75–79]. Circadian rhythms govern fundamental physiological functions in almost all organisms, from prokaryotes to humans. The circadian clocks are intrinsic time-tracking systems with which organisms can anticipate environmental changes and adapt to the appropriate time of day. In mammals, circadian rhythms are generated in pacemaker neurons within the suprachiasmatic nuclei (SCN) and are entrained by light. Disruption of the circadian rhythms can cause depression, insomnia, jet lag, coronary heart disease, and a variety of neurodegenerative disorders (e.g., [95]). Interestingly, peripheral tissues have also been shown to contain independent clocks, the function of which is orchestrated by the SCN [96]. The circadian clocks operate through transcriptional feedback autoregulatory loops that involve the products of circadian clock genes, and following, these genes have been the focus of molecular studies.

The candidate gene literature for sleep phenotypes has focused on fewer genes than that of PTSD; however, there are several candidate genes that have been examined across both phenotypes, representing possible genetic links. Additionally, there are some genes that, despite not being specifically examined in the context of both disorders, have biologically plausible connections to both sleep and PTSD. Candidate genes examined in association with insomnia include circadian genes (e.g., PER3, CLOCK, TIMELESS) and the serotonin transporter (5-HTTLPR), among others, with some success, although few replications [75, 77]. In the following section, we will review the candidate genes with potential relevance to both disorders, and then we discuss the GWAS studies of sleep phenotypes.

In discussing sleep candidate gene research, the first set of genes to consider are the circadian clock genes, given their role in establishing the body’s circadian rhythm. There are mixed results for the CLOCK variant T3111C and sleep disturbances, often studied in the context of mental disorders such as depression. Some results indicate that this polymorphism is associated with decreased sleep, while others do not demonstrate any associations with sleep in depressed individuals [97, 98]. There is also some evidence that the CLOCK gene may be involved in sleep following antidepressant treatment [99]. Although there have not been candidate gene studies explicitly looking at CLOCK in PTSD, the circadian system does influence components of the stress response, particularly glucocorticoid levels, which have their own circadian rhythms (e.g., cortisol typically peaks in the morning) [100]. Landgraf and colleagues [101], in a review of the role of the circadian system in psychopathology, hypothesize that some of the genetic contributions to PTSD vulnerability may result from alterations in CLOCK genes, which disrupt glucocorticoid signaling and in turn affect specific brain regions and alter the stress response. Other gene s involved with glucocorticoid signaling, such as FKBP5, may also be involved through this mechanism [102]. Further, both ADCYAP1R1 and RORA, two other genes examined more thoroughly in the PTSD literature, are related mechanistically to the circadian clock [101]. ADCYAP1R1 is released by the suprachiasmatic nucleus, which entrains the body to light [103], while RORA is released on a circadian rhythm, like glucocorticoids, and also modulates levels of BMAL, another important circadian gene [101].

Widely studied across many phenotypes within psychiatric genetics, the serotonin transporter gene, 5-HTTLPR, has also been implicated in sleep. With regard to sleep problems, carriers of the S allele who were treated with fluoxetine for depression had a higher likelihood of developing insomnia during treatment compared to L allele homozygotes [104]. In a gene-environment interaction approach in a study of caregivers of patients with dementia and non-caregiver controls, Brummett and colleagues [105] found no main effect of 5-HTTLPR genotype on sleep quality but found that caregivers who were S allele carriers were more likely than their L allele caregiver counterparts to report poor sleep. Further, there is evidence that sleep quality and 5-HTTLPR genotype interact to affect temperament in children, which supports an early role of sleep in the development of emotions [106]. There are also several studies examining sleep, depression, and serotonin. Less activity in a MAO-A (an enzyme that degrades serotonin) VNTR has been associated with sleep quality, as well as depression [107]. The 5-HTTLPR genotype has also been shown to influence sleep latency in the elderly, including in the context of depression symptoms [108]. In another study of college students, the triallelic S’S’ genotype was more common in individuals with both shorter sleep and more depressed mood [109]. The serotonin transporter gene may be related to PTSD under high trauma conditions [38], so there is some evidence for its involvement in both sleep and PTSD phenotypes.

Serotonin is also related to BDNF (particularly in psychiatric disorders; [110]), another gene with evidence to suggest that it may be involved in both the development of PTSD and disturbed sleep. As discussed earlier, various studies have examined the Val88Met polymorphism in PTSD, with some showing significance [44]. The BDNF gene may also play a role in disturbed sleep: several studies have demonstrated that individuals with insomnia or fatigue have lower serum BDNF levels, when compared to controls, and that this may even differ by insomnia severity (e.g., [111]). Further, the Val88Met polymorphism itself has been shown to regulate sleep intensity and EEG patterns [112, 113]. A recent review of the BDNF and sleep summarizes the literature by hypothesizing that loss of sleep may cause a decrease in BDNF levels, which in turn alters the ability to respond to stressors, eventually leading to the development of stress-related psychopathology [114].

Another common neurotransmitter examined in the PTSD literature is dopamine. PTSD candidate gene studies suggest that the 9′ allele of the DAT1 polymorphism is related to increased likelihood of PTSD [41, 42, 115], and one study in particular reported that the 9′ allele carriers were at risk primarily driven by the relation to DSM-5 Criterion E symptoms [42], which includes a sleep symptom. There is also support for dopamine receptor genes in PTSD (e.g., DRD2; [116]). Although prior studies of dopamine genes and sleep have mostly utilized animal sleep models (e.g., [117, 118]), current research is highlighting the emerging role of dopamine genes in the context of human sleep phenotypes. DAT1 polymorphisms were associated with higher sleepiness in a young adult sample [119], and dopamine transporter polymorphisms in humans have been linked to the response of the reward system following sleep deprivation [120]. Further, a large, collaborative study of the genetics of sleep duration, which examined 50,000 SNPs from 2000 candidate genes, found evidence for the involvement of the dopamine D2 receptor gene (DRD2) in sleep duration (see [121] for a more thorough review of the results and replication steps).

Other neurotransmitter systems implicated in the genetics of insomnia include gamma-aminobutyric acid (GABA) and orexin/hypocretin [75]. GABRA variants have been shown to interact with lifetime trauma history to predict PTSD [122], and human studies have shown decreased GABA-A receptor binding in certain brain regions of individuals with PTSD [123]. Further, low levels of both serum and cerebrospinal fluid orexin have been shown to be related to combat-related PTSD severity [124]. The comparisons outlined here, although speculative, suggest that based on candidate gene studies, a wide range of neurotransmitter systems may play a role in the genetic overlap between sleep and PTSD and thus warrant future empirical study. A summary can be found in Table 9.2. However, it is important to note that this list is not exhaustive and that many findings have not been replicated.

Similar to PTSD, genome-wide studies of insomnia and sleep-related phenotypes such as sleep quality and sleep duration do exist, although the sleep literature lags behind other psychiatric phenotypes. While there have been eight sleep GWAS to date (excluding sleep disorders other than insomnia, caffeine, and chronotype), there are only two that examine insomnia-related outcomes [125, 126] and one that used actigraphy data [127] and will be discussed in detail here (see Table 9.3). The remaining five focus on sleep duration [128–132], which may be less relevant to PTSD phenotypes: the sleep and PTSD literature indicates that sleep quality is the most relevant sleep outcomes for veterans [133]. Ban and colleagues [125] conducted the first GWAS of an insomnia phenotype using a large Korean sample. There were no loci that passed genome-wide significance, but the most significant SNPs included rs11208305 (ROR1, previously implicated in bipolar disorder) and rs718712 (PLCB1, shown to have associations with schizophrenia). SNPs in CACNA1A, GNAS, NOS3, and ADCY8 were also of interest. Later, Byrne and colleagues [126] conducted a GWAS examining multiple sleep phenotypes (sleep latency, sleep quality, sleep depth, sleep time, sleep duration, insomnia factor score) in an Australian sample. There were no genome-wide significant loci for the insomnia factor score (or other sleep phenotypes), but rs11174478 (in SLC2A13) had the most significant association with the insomnia factor score. The most interesting results were for CACNAIC (a gene previously implicated in bipolar disorder), which had some evidence for an association with both sleep quality and sleep latency in this sample but was not significant in their replication sample. There were no significant results from pathway analysis. However, note that the CACNA1C and sleep quality finding was later replicated by Parsons and colleagues in a British sample [134]. A recent sleep GWAS used a set of objective sleep phenotypes from actigraphy data (as opposed to self-report) [127]. Results, although not corrected for analysis of multiple phenotypes, revealed several genes potentially implicated in regulating sleep efficiency on weekdays (ULF1, which is a circadian gene) and sleep latency (DMRT1). This GWAS is novel in its approach to sleep phenotypes and represents a useful next direction for phenotypes used in genome-wide studies of sleep.

Overall, the insomnia genetic literature suffers from inconsistent phenotypes and small sample sizes [75, 78], which will need to be addressed in future studies. There are few GWAS of insomnia, even compared to PTSD. Results show no genome-wide significant hits for this insomnia or related phenotypes like sleep quality (only GWAS of sleep duration have generated hits). This is in contrast to PTSD, where multiple significant loci have been documented (although not consistently across studies). Thus, it is unsurprising that there have been no common genes identified through GWAS .