This submission contains less information than the section on causes at Attention deficit hyperactivity disorder. Any information on causes that is not already in the article may be added to the article, but only if the information being added has not been copied or closely paraphrased. Robert McClenon (talk) 21:17, 29 January 2019 (UTC)}}

Causes

Most ADHD cases are of unknown causes.^[1]. However, there is strong evidence for genetic and environmental influences on risk ^[2]. In a small fraction of cases, infection, traumatic brain injury, rare chromosomal anomalies or cancer has been linked to changes in behaviour that resemble ADHD ^[3].

Genetics

ADHD runs in families. Siblings of individuals with ADHD show and 8-9 times higher rate of ADHD than siblings of individuals without ADHD^[4]. Twin Studies (comparing identical and non-identical twins) suggest that much of this increased rate comes from genetic, rather than shared environmental, factors. The mean heritability estimated from twin studies is 74% ^[5]. Genetic factors also contribute significantly to the persistence of ADHD from childhood into adulthood ^[6]

ADHD is not caused by a single gene - it is a complex polygenic disorder similar to schizophrenia, diabetes and most other human medical conditions ^[7]. This means that likely thousands or tens of thousands of genetic variants exist, most of which have a very small effect, contribute to risk for developing ADHD. The risk of having ADHD increases with the number of variants a person has ^[8]. The current view is that many common variants, that have very small individual effects, and some very rare variants, some of which may confer much greater risk, both contribute to the risk of ADHD ^[9].

The initial searches for the source of genetic risk for ADHD found few robust genetic risk loci. Linkage studies were the first to look for regions of genetic rick across the whole genome, although few genome-wide significant regions were identified ^[10]. Candidate gene approaches focused on genes related to dopamine and norepinephrine (given the pharmacological action of medications for ADHD), as well as other neurotransmitter systems (e.g. serotonin) and genes involved in synaptic function. Despite some encouraging initial findings, most candidate gene study findings were not replicated ^[11], and none meet current standards of evidence.

Microarray studies of common single nucleotide polymorphisms (SNPs; typically those with an allele frequency greater than 1% across the genome. Such genome-wide association studies (GWAS) have been performed now for over a decade, with the first study published in 2008 ^[12]. Until recently, all GWAS of ADHD were underpowered, however, and only in 2018, the first genome-wide significant risk loci were published, based on a large international collaboration between the Psychiatric Genomics Consortium (PGC) and iPSYCH (Denmark) ^[13]. This study of 20,183 cases and 35,191 controls identified 12 independent rick loci including variants in or close to FOXP2, DUSP6, and SEMA6D, although the precise biological consequences of these associated variants are yet known. Genes in these loci have been implicated in synapse formation, neurotransmission, and brain development. Overall, the genetic variants associated with ADHD were enriched in evolutionarily constrained genomic regions, loss-of-function intolerant genes, and around brain-expressed regulatory marks. Collectively, thousands of common genetic variants accounted for 22% of risk for ADHD, further supporting the polygenic nature of ADHD.

Rare variants (frequency less that 1%) may also play a role in ADHD. Clearly, ADHD symptoms are common in syndromes arising from rare chromosomal anomalies including Frigile Z, aneuploidies (Down Syndrome, Klinefelter syndrome, Turner syndrome), 22q11.2 deletion syndrome, and Tuberous Sclerosis, among others ^[14]. Burden of rare copy number variants (CNVs) may be associated with ADHD patients ^[15] but . Whole exome sequencing (WES) studies also implicate rare missense and protein-truncating variants in ADHD ^[16].

ADHD shared genetic risk with other brain conditions and behavioural traist, including major depressive disorder, anorexia, migranes, smoking, and lower educational outcomes, but also with somatic medical conditions, like obesity and lung cancer ^[17]. Rare variant analyses also indicate that CNVs linked to ASD and schizophrenia are enriched in ADHD ^[18]. These results suggest that ADHD may co-occur with certain conditions and traits because of shared genetic factors. Diagnostically distinct conditions may also have some common underlying biological mechanisms.

ADHD symptoms are not only present in ADHD but are also widely distributed in the general population ^[19]. AHD is thought to represent the extreme end of the traits ^[20]. Consistant with such continuity from behavioural traits to clinical disorders, the genetic risk variants for diagnosed ADHD appear to be shared with ADHD symptoms in the general population ^[21]

Preliminary evidence suggests that genetic factors also influence the response to pharmalogical treatment for ADHD. For example, genetic variants have been associated with greater efficacy and ability to metabolize medications for ADHD ^[22]. However, most studies in this field of pharmacogenetics are still underpowered.

• The Colóns (2002-2010)
• The Colóns (2017)
• The Colóns Brothers
• The Colóns (disambiguation)
• The Combat (1926 film)
• The combat of the 30
• The Comber Greenway
• The Combine (Half-Life)
• The Comb of the Wind
• The Comcast Network
• The Come Back
• The Comeback (2001 film)
• The Comeback (2015 film)
• The Come Back, All is Forgiven Tour: Live
• The Comeback (film)
• The Comeback (song)
• The Comeback (The Waltons)
• The Comedian (2016 film)
• The Comedian (2017 film)
• The Comedian (film)
• The Comedian's Child
• The Comedian's Guide to Survival
• The Comedown
• The comedy
• The Comedy About a Bank Robbery