Associations between Autism Spectrum Problems and comorbid somatic problems across the lifespan

Autism Spectrum Disorder (ASD) is a common and high-cost neurodevelopmental disorder with lifelong impacts, affecting 1-1.5% of individuals (1, 2). Somatic comorbidities are common in individuals with ASD, such as immune and gastrointestinal (GI) problems (3), causing elevated symptoms burden, reduced ability to work, and overall decreased length and quality of life. More than 70% of individuals with ASD have concurrent somatic, psychiatric, or developmental comorbidities (4). The associations between ASD and somatic problems are complex and likely to be bidirectional. Co-morbid somatic problem may cause or enhance the symptoms of ASD, and ASD can be an early entry point for developing different kinds of comorbidities (4, 5). Individuals with ASD often have higher risks of suffering somatic comorbidities across the entire life course (6, 7). Studies focusing on somatic comorbidities in ASD cross the lifespan could be of major value for understanding disease etiology and improvement of diagnosis, treatment, and prevention of ASD and somatic comorbidities. The aim of our study is to enhance the knowledge on the somatic comorbidities of ASD at the phenotypic and the genetic level. 
So far, the literature has shown that Gastrointestinal (GI) symptoms, food allergy, and inflammatory or immunological disorders are more common in children with ASD compared with the neurotypical children. A recent review study of 18 original studies indicated that 83% of children across these studies reported the significant increased prevalence of GI symptoms in individuals with ASD (8). Constipation was the most frequently reported symptom, followed by diarrhea. Similarly, a meta-analysis study reported that the OR for ASD in individuals with food allergy was 2.22 compared with the control group, revealing a substantial relationship between food allergy and ASD (9). In addition, multiple studies have shown a higher prevalence of immunological conditions in individuals with ASD compared to the general population. These immunological conditions include asthma, other allergies, type I diabetes, coeliac disease, and rheumatoid arthritis (10). However, these are less well researched than the GI symptoms and food allergies. For all of these somatic condition it holds that almost all the existing studies have been conducted among children with ASD, and very few concerned adults. 
Additionally, individuals with ASD may have a disproportional rate of co-occurring pain and fatigue. ASD has been linked to sensory abnormalities, such as hyper-responsiveness to minor stimuli, which may contribute to the onset of co-morbid pain and fatigue (11-14). Literature has also suggested that these sensory symptoms were related to abdominal pain in ASD (15). A higher rate of abdominal pain was reported in ASD children (OR=2.45) in a meta-analysis study (16). Another small study showed increased pain in general in individuals with ASD rather than abdominal pain (17). Thus, there is some evidence revealing an association between abdominal pain and ASD, which may be linked to comorbid GI problems, and few studies have addressed the link with pain and ASD in general. Studies looking into fatigue have so far been very few and with mixed findings: one study reported an association with ASD (18), but another did not (19). Both studies were based on small samples. Therefore, the relationship between fatigue and ASD is inconclusive, but deserves further study.
Although the biological mechanisms of comorbid somatic disorders in ASD have not been elucidated, recent genetic research have suggested that genetic overlap between ASD and other phenotypes may be at the basis of these problems in ASD. Existing evidence have identified modest joint genetic associations between autism and other neurodevelopmental and mental conditions such as schizophrenia, attention-deficit/hyperactivity disorder (ADHD), and major depression (2, 20). However, studies exploring the polygenic associations between ASD and comorbid somatic disorders have so far been very few. One study has found significant genetic correlation (r=.33) between ASD and tiredness (21). These evidences suggested the potential genetic contribution in con-current somatic problems in ASD and our aim is to extend these findings by studying associations based on polygenic risk scores. We will relate polygenic risk scores of comorbid somatic diseases to ASD and vice versa, the polygenic risk score of ASD to somatic diseases.
In sum, while associations between ASD, GI symptoms, pain, fatigue and immune related diseases have been reported, these need to be better established, especially in adults. Furthermore, to improve our understanding of the causes of these comorbidities, studies to evaluate genetic sharing of ASD and somatic problems are needed. We will use the large-scale and detailed phenotypic and genetic data in Lifelines for our research. The findings will improve our understanding of the somatic health profile of ASD across the lifespan and will contribute to establishing the genetic associations that may exist between somatic health and ASD.