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New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders
GWAS use a ‘hypothesis-free’ design by genotyping hundreds of thousands to 2 million markers simultaneously in cases and controls. This approach generates large amounts of data and creates issues with regard to multiple testing. As a result, early GWAS in psychiatric phenotypes yielded negative findings (Sklar et al., 2008; Craddock and Sklar, 2013). In retrospect, those studies (despite sample sizes in the range of 1000–2000) were largely underpowered to detect risk variants of small effect.
- This increased risk is likely due in part to shared genetic factors, but it may also be related to environment, lifestyle, and other nongenetic influences that are shared by members of a family.
- Substance use disorder (SUD) is a treatable mental disorder that affects a person’s brain and behavior, leading to their inability to control their use of substances like legal or illegal drugs, alcohol, or medications.
- Alcohol use disorder (AUD) often seems to run in families, and we may hear about scientific studies of an “alcoholism gene.” Genetics certainly influence our likelihood of developing AUD, but the story isn’t so simple.
- The E504K variant disrupts the hydrogen bonding network between E504 and residues, R281 and R492, leading to a change in conformation of these residues at the dimer interface (Fig. 4H).
- And these distinctions will be important for identifying the genetics of addiction, the researchers said.
Whole genome sequencing
Several study designs—including case–control studies, population studies, and family studies—have been used to test whether a specific gene or gene variant affects risk for a disease (for more information, see the article by Foroud and Phillips, pp. 266–272). For example, it is much easier to collect individual cases (i.e., people with alcoholism) and control subjects (i.e., nonalcoholic people) or samples of the general population than it is to recruit family samples. On the other hand, family studies avoid the problem of incomplete ethnic/population matching1 that can confound celebrities with fetal alcohol syndrome case–control studies. Furthermore, family studies can be more powerful than case–control studies if different variants (i.e., alleles) of the same gene affect a given trait in different families, because multiple families can show an effect of that gene despite not sharing the same alleles. In addition, broad regions of the genome generally are inherited within a family, increasing the sensitivity of the approach to detect an effect; however, the tradeoff is that for the same reason, family studies have less resolution to identify the specific allele(s) involved.
NIH-funded intervention did not impact opioid-related overdose death rates over evaluation period
One sample using male twins from the Vietnam Era Twin Registry reported different heritability estimates for 23 symptoms of alcohol dependence, further highlighting the heterogeneity of AUD (Slutske et al., 1999). The purpose of the Collaborative Study on the Genetics of Alcoholism (COGA) is to advance knowledge about the complex influences of gene and environment on development and progression of alcohol use disorder (AUD). From its inception, COGA has generated and utilized extensive arrays of genotypic and phenotypic data from families densely affected by AUD and from comparison families to identify genes and understand their role in susceptibility to (or protection from) developing AUD and related phenotypes. New genetic variants have been identified, refined endophenotypes have been characterized, and functional information has begun to emerge on known genetic variants that influence risk for and protection from AUD.
What Increases the Risk for Alcohol Use Disorder?
Linkage studies are relatively robust to populationdifferences in allele frequencies (because they test within-family inheritance), andcan find a signal even if different variants in the same gene or region areresponsible for the risk in different families. The drawback to this approach isthat linkage studies find broad regions of the genome, often containing manyhundreds of genes. In many cases, the initial linkage studies were followed by moredetailed genetic analyses employing single nucleotide polymorphisms (SNPs) that weregenotyped at high density across the linked regions. Some of the genes identifiedthrough this approach have been replicated across a number of studies and appear tobe robust genetic findings. Alcohol is widely consumed, but excessive use creates serious physical,psychological and social problems and contributes to many diseases.
Factors influencing AUD
But such stories often were dismissed as mothers being forgetful, if not outright lying. The researchers believe that even larger studies may help to differentiate the genetics behind alcohol addiction. Variations in many other genes also have been implicated in contributing to alcoholism risk.
Golding has also found evidence in mice that paternal alcohol use can lead to other changes in sperm that affect foetal growth. He and his colleagues have found that chronic alcohol use alters the ratio of inherited fragments a type of genetic material called RNA in sperm. Beyond that, Palmer and his team want to develop a better understand of how the genes they’ve identified might influence these traits, but using animal and cellular models. Researchers at the University of California at San Francisco (UCSF) are using fruit flies to find the genetic causes of alcoholism. According to scientists, drunken drosophila fruit flies behave the same way humans do when they are drunk. In addition, a fruit fly’s resistance to alcohol appears to be controlled by the same molecular mechanism as humans.
The tetramer functions as a dimer of dimers, where each of the four monomeric subunits contains a dinucleotide (NAD+)-binding domain, oligomerization domain and a catalytic domain with three key cysteine residues and a glutamate, which are required for the catalysis at the active site [34]. To determine whether wild type ALDH2 or the variants can form dimers and tetramers in solution, we employed a cross linker, bis(sulfosuccinimidyl)suberate, to capture these two forms of ALDH2. Furthermore, we performed western blot analysis of the crosslinked proteins to determine the presence of S-tagged proteins expressed with the petDuet-1 plasmid. A western blot with the S-tag antibody showed that R101G formed few dimers and tetramers relative to wild type and WT/E504K (Fig. 6A and Supplementary Fig. 1A). Additionally, there was no significant difference between dimers and tetramers of WT/R114W compared to wild type or WT/E504K using the S-tag antibody (Fig. 6A). When using an ALDH2 antibody to detect proteins expressed in the His-tag and S-tag cloning sites of petDuet-1 plasmid, WT/R101G formed dimers and tetramers albeit at a lower level compared wild type or WT/E504K (Fig. 6B and Supplementary Fig. 1B).
In wild-type ALDH2, R101 of one subunit forms a hydrogen bond with S517 of the opposite ALDH2 subunit via a conserved water molecule, while R114 forms an H-bond with E227 of the same subunit (Fig. 4C and D). The E504 residue form hydrogen bonds with R281 of the same subunit and R492 of the adjacent dimer partner [34]. When R101 is mutated to a glycine, a hydrogen bond via a conserved water molecule is lost between R101 and S517 (Fig. 4F).
Alcohol use disorder is a broad diagnosis that encompasses several commonly used terms describing problems with drinking. It includes alcoholism, also called alcohol addiction, which is a long-lasting (chronic) condition characterized sober houses in boston by a powerful, compulsive urge to drink alcohol and the inability to stop drinking after starting. In addition to alcoholism, alcohol use disorder includes alcohol abuse, which involves problem drinking without addiction.
It would also have “real benefit… because we know that one of the key determinants of a woman drinking in pregnancy is if her male partner [if she has one] is drinking in pregnancy”, she says. “Which makes sense – remember, these babies have never been [directly] exposed to alcohol,” Huffman says. “But look.” On screen, she pulls up images of the mouse offspring’s neocortexes – the part of the brain involved in higher functions. In control mice whose parents weren’t exposed to alcohol, the primary somatosensory cortex – part of the brain that responds as it receives input from the mouse’s whiskers – was in a distinctly different area to the primary visual cortex, which interprets visual cues. If a mouse mum consumed alcohol in pregnancy, her offspring showed some of the physiological symptoms of FASD that might be expected. But some changes in both cranial-facial patterning and in overall growth got worse when both parents drank.
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